GENOMIC
Mapping
5q14.1. View the map and BAC contig (data from UCSC genome browser).
Structure
(assembly 07/03)
AP3B1/NM_003664: 27 exons, 292,378 bp, chr5:77,382,224-77,674,601.
The figure below shows the structure of the AP3B1 gene (data from UCSC genome browser).
Regulatory Element
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
TRANSCRIPT
RefSeq/ORF
AP3B1/NM_003664: 4,009bp, view ORF and the alignment to genomic.
Note: This RefSeq entry is based on AP3B1 entry BC038444 (4021bp), which matches a transcript (gi: 24638436), but exhibits differences between BC038444 and the human genome build 34. The encoded two proteins present one amino acid difference (E585V).
Expression Pattern
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
5q14.1. View the map and BAC contig (data from UCSC genome browser).
Structure
(assembly 07/03)
AP3B1/NM_003664: 27 exons, 292,378 bp, chr5:77,382,224-77,674,601.
The figure below shows the structure of the AP3B1 gene (data from UCSC genome browser).
Regulatory Element
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
TRANSCRIPT
RefSeq/ORF
AP3B1/NM_003664: 4,009bp, view ORF and the alignment to genomic.
Note: This RefSeq entry is based on AP3B1 entry BC038444 (4021bp), which matches a transcript (gi: 24638436), but exhibits differences between BC038444 and the human genome build 34. The encoded two proteins present one amino acid difference (E585V).
Expression Pattern
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
(assembly 07/03)
AP3B1/NM_003664: 27 exons, 292,378 bp, chr5:77,382,224-77,674,601.
The figure below shows the structure of the AP3B1 gene (data from UCSC genome browser).
Regulatory Element
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
TRANSCRIPT
RefSeq/ORF
AP3B1/NM_003664: 4,009bp, view ORF and the alignment to genomic.
Note: This RefSeq entry is based on AP3B1 entry BC038444 (4021bp), which matches a transcript (gi: 24638436), but exhibits differences between BC038444 and the human genome build 34. The encoded two proteins present one amino acid difference (E585V).
Expression Pattern
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
TRANSCRIPT
RefSeq/ORF
AP3B1/NM_003664: 4,009bp, view ORF and the alignment to genomic.
Note: This RefSeq entry is based on AP3B1 entry BC038444 (4021bp), which matches a transcript (gi: 24638436), but exhibits differences between BC038444 and the human genome build 34. The encoded two proteins present one amino acid difference (E585V).
Expression Pattern
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
AP3B1/NM_003664: 4,009bp, view ORF and the alignment to genomic.
Note: This RefSeq entry is based on AP3B1 entry BC038444 (4021bp), which matches a transcript (gi: 24638436), but exhibits differences between BC038444 and the human genome build 34. The encoded two proteins present one amino acid difference (E585V).
Expression Pattern
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Tissue specificity: ubiquitous. Highest and lowest expression in kidney and liver tissue respectively.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
PROTEIN
Sequence
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Beta3A-adaptin (NP_003655): 1094aa, ExPaSy NiceProt view of Swiss-Prot:O00203.
Synonyms: Adapter-related protein complex 3 beta 1 subunit; Adaptor protein complex AP-3 beta-1 subunit; AP-3 complex beta-1 subunit; Clathrin assembly protein complex 3 beta-1 large chain.
Ortholog
Species
Mouse Dog Rat Fruitfly Yeast GeneView
pe/Ap3b1 AY221640 Ap3b1 CG11427 (rb) APL6 Protein
NP_033810 (1105aa) AAP45786 (1091aa) XM_226666 (1171aa) AAF71924 (1160aa) Apl6p (809aa) Identities
86% /965aa 93% /1020aa 82% /972aa 49% /569 27% /223
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
| Species | Mouse | Dog | Rat | Fruitfly | Yeast |
| GeneView | pe/Ap3b1 | AY221640 | Ap3b1 | CG11427 (rb) | APL6 |
| Protein | NP_033810 (1105aa) | AAP45786 (1091aa) | XM_226666 (1171aa) | AAF71924 (1160aa) | Apl6p (809aa) |
| Identities | 86% /965aa | 93% /1020aa | 82% /972aa | 49% /569 | 27% /223 |
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
Domain
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
(1) Domains predicted by SMART:
a) low complexity: 277 - 296
b) low complexity: 677 - 733
c) low complexity: 756 - 806
d) low complexity: 852 - 862
(2) Transmembrane domains predicted by SOSUI: none.
(3) Pfam domains: PF01602 - Adaptin N terminal region.
(4) Graphic view of InterPro domain structure.
(5) CDD domain: KOG1060: Vesicle coat complex AP-3, beta subunit [Intracellular trafficking, secretion, and vesicular transport].
Motif/Site
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
75 - 78 NASE, 401 - 404 NIST, 907 - 910 NNTT, 908 - 911 NTTD, 1004 - 1007 NETS.
b) Tyrosine sulfation site [rule] [Warning: rule with a high probability of occurrence]:
267 - 281 edngknfYesdddqk.
c) cAMP- and cGMP-dependent protein kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
741 - 744 KRnS, 795 - 798 RRvT. Evidence shown the protein is phosphorylated on serine residues.
d) Tyrosine kinase phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
344 - 351 RsnrEvq.Y
e) GLU_RICH Glutamic acid-rich region [profile]:
678 - 802.
f) SER_RICH Serine-rich region [profile]:
677-794.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: found KLPI at 923
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: too long tail
i) Dileucine motif in the tail: found, LL at 114.
3D Model
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
ModBase: predicted comparative 3D structures on O00203 (data from UCSC Gene Sorter). (from left to right: Front, Top, Side view)
2D-PAGE
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=121,320Da, pI=5.75 (NP_003655).
FUNCTION
Ontology
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
a) Biological process: intracellular protein transport (overview of trafficking pathway here).
b) Biological process: endocytsis
c) Component of Golgi apparatus.
d) Plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
e) Plays a role in the vesicular trafficking of tyrosinase to melanosomes (view diagram of melanosomal protein sorting here).
Location
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Component of the coat surrounding the cytoplasmic face of coated vesicles located at the Golgi complex.
Interaction
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2).
In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
The HPS2/AP3B1 gene encodes the adapter-related protein complex 3 beta 1 subunit (beta-adaptin 3A, or AP-3 complex beta-3A subunit). The AP-3 complex is a heterotetramer composed of two large adaptins (delta/AP3D1 and beta3A/AP3B2 or beta3B/AP3B1), a medium adaptin (mu3A/AP3M1 or mu3B/AP3M2) and a small adaptin (sigma3A/AP3S1 or sigma3B/AP3S2). In addition, the AP3M1 subunit interacts with tyrosinase for lysosomal targeting (Honing, et al). Sugita, et al showed that CD1B, but not other CD1 isoforms, binds the AP3 adaptor protein complex.
6 proteins are shown to be associated with APL6 in Yeast GRID.
AP3B1 drosophila homolog CG11427 interaction information in CuraGen interaction database.
Pathway
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
AP-3 complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles (view diagram of AP-3 pathway here). Sugita, et al concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.
It is proposed that AP-3 facilitates membrane recruitment of BLOC-1, which in turn facilitates AP-3 (and BLOC-2) dissociation. It seems that BLOC-1 might serve as a tethering factor downstream of AP-3-mediated vesicle formation (Di Pietro, et al).
MUTATION
Allele or SNP
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Mutational alleles described in HGMD.
Allelic variants described in OMIM.
SNPs deposited in dbSNP.
Distribution
Location
Genomic
cDNA
Protein
Type
Strain
Reference
Exon 8
904A>T
904A>T
R302X
nonsense
Dutch
Enders, et al
Exon 10
1062AdelCA ins TATCAATATC
1062AdelCA ins TATCAATATC
Q355delCA ins TATCAATATC
frame-shift, 360X
Italian
Fontana, et al
Exon 12
1166A~1128C del 63bp
1166A~1128C del 63bp
390L-410Q del 63bp
in-frame
Dutch
Dell'Angelica, et al
Intron 14
splicing donor, +6 T>C
1473Tins 39bp
T491ins 39bp
frame-shift, 496X
English
Clark, et al
Exon 15
1525C>T
1525C>T
R509X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
Exon 15
1618GinsG
1618GinsG
G540insG
frame-shift, 565X
English
Clark, et al
Exon 16
1739T>G
1739T>G
L580R
missense
Dutch
Dell'Angelica, et al
Exon 16
1789AinsA
1789AinsA
I597insA
frame-shift, 608X
Italian
Fontana, et al
Exon 18
1975G>T
1975G>T
E659X
nonsense
Cajun/Houma Indian
Huizing, et al (2002)
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_003664.)
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
| Location | Genomic | cDNA | Protein | Type | Strain | Reference |
| Exon 8 | 904A>T | 904A>T | R302X | nonsense | Dutch | Enders, et al |
| Exon 10 | 1062AdelCA ins TATCAATATC | 1062AdelCA ins TATCAATATC | Q355delCA ins TATCAATATC | frame-shift, 360X | Italian | Fontana, et al |
| Exon 12 | 1166A~1128C del 63bp | 1166A~1128C del 63bp | 390L-410Q del 63bp | in-frame | Dutch | Dell'Angelica, et al |
| Intron 14 | splicing donor, +6 T>C | 1473Tins 39bp | T491ins 39bp | frame-shift, 496X | English | Clark, et al |
| Exon 15 | 1525C>T | 1525C>T | R509X | nonsense | Cajun/Houma Indian | Huizing, et al (2002) |
| Exon 15 | 1618GinsG | 1618GinsG | G540insG | frame-shift, 565X | English | Clark, et al |
| Exon 16 | 1739T>G | 1739T>G | L580R | missense | Dutch | Dell'Angelica, et al |
| Exon 16 | 1789AinsA | 1789AinsA | I597insA | frame-shift, 608X | Italian | Fontana, et al |
| Exon 18 | 1975G>T | 1975G>T | E659X | nonsense | Cajun/Houma Indian | Huizing, et al (2002) |
Effect
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20.
PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print]
PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008
Most of the reported patients are compound heterozygotes except one patient with homozygous R302X mutation. The nonsense mutations (R509X and E659X) produce no mRNA and no AP3B1 protein (Huizing, et al (2002) ). The double heterozygous mutations (Δ 390-410 and L580R) in two brothers produce normal amounts of AP3B1 mRNA but exhibite drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A (Dell'Angelica, et al ). The patient with the splice site mutation (T>C) and G540insG might have a very small amount of wild-type protein, but they could not find beta3A, gamma, or mu3A, three subunits of the AP-3 complex , indicating that loss of the beta3A subunit induces instability of the complex and rapid degradation of other subunits (Clark, et al). The two patients with a compound mutation (Q355fsX360; I597fsX608) show a complete absence of beta-3A (Fontana, et al).
PHENOTYPE
Defects in AP3B1 are the cause of Hermansky-Pudlak syndrome type 2 (HPS-2, OMIM 608233 ) (Dell'Angelica, et al). All HPS-2 patients so far reported have oculocutaneous albinism, absent platelet dense bodies, and distinguishing feature of neutropenia. HPS-2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS-2 have an increased susceptibility to infections. The degranulation defect of CTL and NK cells impairs lysis of targeted cells. Mild facial dysmorphia, hepatosplenomegaly, developmental delay, and pulmonary fibrosis have been reported (Huizing, et al (2002) ). Hemophagocytic lymphohistocytosis (HLH), which represents lysosomal trafficking disorder, has also been reported in HPS-2 patients (Enders, et al; Ma, et al).
HPS-2 fibrablasts exhibit increased surface expression (mislocalization) of lysosomal proteins (e.g. CD63, LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane (Dell'Angelica, et al). HPS-2 melanocytes showed tyrosinase was restricted to the perinuclear region (Huizing, et al (2001) ). Misorting of lysosomal proteins such as CD63 or CD107 to the cell membrane has been found on fibroblasts,neutrophils or CTLs. Neutrophil elastase (NE) and perforin content are reduced in HPS-2 patients, and the cytolytic activity of NK cells are impaired. These suggest the impaired innate immunity in HPS-2 (Fontana, et al; Jung, et al). NE appears to be one of the cargo proteins of AP-3 complex (Horwitz, et al).
In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. The defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients (Sugita, et al) (view diagram of CD1B blockage in APC cells here). By studying CD8-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark, et al determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing (view diagram of lytic granule blockage in CTL cells here).
REFERENCE
- Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 4: 1111-20. PMID : 14566336
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21. PMID: 10024875
- Di Pietro SM, Falcon-Perez JM, Tenza D, et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17:4027-38. PMID: 16837549
- Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Muller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak Syndrome Type II. Blood 2006; 108: 81-7. PMID: 16551969
- Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, Benassi M, Gentili F, Ferrari D, Notarangelo LD, Cavadini P, Marcenaro E, Dusi S, Cassatella M, Facchetti F, Griffiths GM, Moretta A, Notarangelo LD, Badolato R. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-64.PMID: 16507770
- Honing S, Sandoval IV, von Figura K. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J 1998; 17: 1304-14. PMID: 9482728
- Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia.Blood. 2006 Nov 14; [Epub ahead of print] PMID: 17053055
- Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell 2001; 12: 2075-85. PMID: 11452004
- Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, Gahl WA. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-8. PMID: 11809908
- Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam C, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006; 108: 362-9.PMID: 16537806
- Ma D, Rudd E, Edner J, Gavhed S, Ramme KG, Fadeel B, Nordenskj?ld M, Henter JI, Zheng C. Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; [Epub ahead of print] PMID: 18000860
- Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 2002; 16: 697-706. PMID: 12049721
EDIT HISTORY:
Created by Wei Li: 06/21/2004
Updated by Wei Li: 04/05/2006
Updated by Wei Li: 12/25/2006
Updated by Wei Li: 10/08/2007
Updated by Wei Li: 02/29/2008