5qF View the map and BAC clones of FISH (data from UCSC genome browser).
Hps4/NM_138646: 13 exons, 33,463 bp, chr5:111,385,848-111,419,310.
The figure shows the structure of le gene. (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (seq1=human HPS4, seq2=mouse Hps4) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
Highly expressed in heart, brain, liver and testis. Expressed at lower level in skeletal muscle. 3.6 kb and 3.1 kb transcripts were observed on Northern-blot analysis (Suzuki, et al).
Affymetrix microarray expression pattern in SymAtlas from GNF is shown below.
|Protein||NP_071364 (708aa)||24438 (708aa)||XP_222245 (545aa)||08962 (673aa)||NP_956620 (647aa)||Q8MT61 (834aa)|
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
(1) Domains predicted by SMART:
a) low complexity: 171-180
b) low complexity: 467-486
c) low complexity: 514-529
(2) Transmembrane domains predicted by SOSUI: none.
(1) Predicted results by ScanProsite:
a) N-glycosylation site [pattern] [Warning: pattern with a high probability of occurrence]:
616 - 619 NAST
b) Protein kinase C phosphorylation site [pattern] [Warning: pattern with a high probability of occurrence]:
104 - 106 ScR, 153 - 155 ShR, 210 - 212 TaK, 341 - 343 SsR, 411 - 413 SgR, 472 - 474 SsR, 495 - 497 SgR, 613 - 615 TiR, 639 - 641 TaR.
(2) Predicted results of subprograms by PSORT II:
a) N-terminal signal peptide: none, N-terminal side will be inside.
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: none
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: none
i) Dileucine motif in the tail: none
(1) ModBase: none.
(2) 3D models of protein predicted by SPARKS (fold recognition) below. View the models by PDB2MGIF.
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=72,634Da, pI=5.17.
a) Biological process: melanocyte differentiation, organelle organization and biogenesis.
b) Component of cytoplasmic vesicle.
Cytoplasm, may be associated with membrane fraction.
HPS4p is a component of a protein complex termed biogenesis of lysosome-related organelles complex 3 (BLOC-3), where HPS1p is residing as another subunit (Chiang, et al; Martina, et al; Nazarian, et al) (view diagram of BLOC-3 complex here). The BLOC-3 complex is a moderately asymmetric complex with a molecular mass of about 175 kD. The BLOC-3 complex dissociates into smaller complex (BLOC-4) upon Tris treatment and a portion of HPS1 exists in a cytosolic complex (BLOC-5) that does not contain HPS4 (Chiang, et al).
No interactions found in the CuraGen database by searching its drosophila homolog CG4966.
Hps4 may be involved in the biogenesis of early melanosomes and the maturation (view diagram of melanosome blockage here) or the structure of cytoplasmic organelles, i.e. melanosomes, platelet dense bodies, lysosomes. Suzuki, et al revealed that Hps4 and Hps1 proteins function in the same pathway of organelle biogenesis. However, the exact mechanism of BLOC-3 in melanosomal biogenesis is lacking. Martina, et al found that Hps1 and Hps4 are components of a cytosolic complex that is involved in the biogenesis of lysosomal-related organelles through a mechanism distinct from that operated by the AP-3 complex (view diagram of BLOC-3 and AP-3 pathway here).
SNPs deposited in dbSNP.
|Exon 3||148C>T||148C>T||Q50X||nonsense||le (B6)||Suzuki, et al|
(Numbering of genomic and cDNA sequence is based on the start codon of RefSeq NM_138646.)
The nonsense Q50X mutation in the Hps4 gene is predicted as nonsense mediated decaying. The Hps1p protein is absent in tissues of le mutant mice (Suzuki, et al).
Defects in Hps4 are the cause of the light ear (le) mutant. Homozygotes for a spontaneous null mutation exhibit hypopigmentation, prolonged bleeding associated with a platelet defect, reduced secretion of kidney lysosomal enzymes, and resistance to diet-induced atherosclerosis (Novak, et al; Paigen, et al). See more details in the Mouse Locus Catalog#Hps4. The strain is described in more detail in JAX Mice database (B6.-Hps4le/J). le and ep mutants have identical phenotypes. Very few melanosomes of the retinal pigment epithelium (RPE) are observed in the BLOC-3 mutants Hps1/ep and Hps4/le. A unique feature of ep and le is the presence of very large macromelanosomes within the choroids ( Suzuki, et al). In addition, le/le-ep/ep double-homozygote mice have a phenotype identical to the two homozygous single mutants (Meisler, et al).