11q14.3. View the map and BAC clones (data from UCSC genome browser).
TYR/NM_000372: 5 exons, 118,207bp, Chr11: 88,598,773 - 88,716,979.
The figure below shows the structure of the TRY gene (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
Tissue specificity: Highest expression in skin tissue. Increased expression after UV-B radiation.
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 )
|Identities||85% /457aa||86% /461aa||87% /462aa|
|Identities||73% /389aa||61% /324aa||27% /73aa|
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
(1) Domains predicted by SMART:
a) signal peptide 1-18
b) Pfam: Tyrosinase 111-456
c) tansmembrane 474-498
(2) Transmembrane domains predicted by SOSUI: Two transmembrane helices detected.
|No.||N terminal||transmembrane region||C terminal||type||length|
(3) Graphical view of InterPro domain structure.
(1) Predicted results by ScanProsite:
a) EGF-like domain signature 1 :
89 - 100: CqCsgnfmGfnC
b) Laminin-type EGF-like (LE) domain signature :
89 - 112: Cq.CsgnfmGfnCgnCkfgfWgpn............C
c) Tyrosinase CuA-binding region signature :
202 - 219: Heapa.FLpWHRlfLlrwE
d) Tyrosinase and hemocyanins CuB-binding region signature :
383 - 394: DPiFLlhHafvD
e) Protein kinase C phosphorylation site : [occurs frequently]
26 - 28: SsK, 50 - 52: SgR, 113 - 115: TeR, 309 - 311: TpR, 339 - 341: SfR, 441 - 443: SsK.
f) N-glycosylation site : [occurs frequently]
86 - 89: NRTC, 111 - 114: NCTE, 161 - 164: NGST, 230 - 233: NFTI, 337 - 340: NFSF, 371 - 374: NGTM.
g) Microbodies C-terminal targeting signal : [occurs frequently]
527 - 529: SHL
h) Tyrosine sulfation site : [occurs frequently]
442 - 456: skdlgydYsylqdsd
Note: The above scan shows two binding regions which correspond to the 2 copper ion cofactors present per subunit
(2) Predicted results of subprograms by PSORT II:
a) Seems to have a cleavable signal peptide (1 to 17)
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: found at 520 and 524
i) Dileucine motif in the tail: found LL at 514
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=60,393Da, pI=5.71 (NP_000363, precursor).
a) Biological process: eye pigment biosynthesis; melanin biosynthesis from tyrosine
b) Biological process: visual perception
c) Monophenol monooxygenase activity
d) Component of Golgi vesicle
e) Integral to membrane
Type I membrane protein. Melanosome.
Tyrosinase binds 2 copper ions per subunit (CuA and CuB). Tyrosinase is activated when protein kinase C-beta (PKC-beta) phosphorylates the serine residues at amino acid positions 505 and 509. Phosphorylation of tyrosinase by PKC-beta induces a complex formation between tyrosinase and TYRP1 (Wu, et al). The p protein regulates posttranslational processing of tyrosinase, and hypopigmentation in melan-p1 cells is the result of altered tyrosinase processing and trafficking (Chen, et al, Toyofuku, et al).
Tyrosinase (Monophenol monooxygenase, EC 184.108.40.206) is a glycoprotein and a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. It catalyzes the rate-limiting conversions of tyrosine to dopa, dopa to dopa-quinone and possibly 5,6-dihydroxyindole to indole-5,6 quinone (L-tyrosine + L-DOPA + O2 = L-DOPA + DOPAquinone + H2O).
During the melanogenesis, tyrosinase can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which tyrosinase is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system (Watabe, et al). Tyrosinase is sorted via the dilucine signal to the melanosomes for melanin synthesis mediated by AP-3 complex (view diagram of melanosome maturation in melanocytes here).
The distribution of mutations and polymorphisms is described in detail in Albinism Database. For cross-reference, view the distribution of mutations and polymorphisms in the Retina International Mutation Database of TYR Gene.
54 novel mutations not appeared in the HGMD database:
(1) Chaki, et al (2006) reported 5 novel mutations (D42N, C91S, E219K, Q326X, G372R) in Indian OCA1 patients.
(2) Hutton, et al (2008a) analyzed Caucasian patients with autosomal recessive ocular albinism (AROA). All were compound heterozygotes with one R402Q allele. One novel mutation (c.47delC) was reported.
(3) Hutton, et al (2008b) reported 8 novel mutations, one frameshift (c.124delG) and seven missense substitutions (F84V, I123T, Y149C, Y181C, H202R, P209L, and L288F) in Caucasian OCA1 patients. They excluded the P152S from a pathological mutation. Among the non-Hispanic Caucasian OCA1 patients, the T373K mutation was most frequent (13.7%). T373K is by far the most frequent OCA1A mutant allele, followed by P81L. V275F and IVS2-7T are the most frequent OCA1B mutant alleles.
(4) Wang, et al (2009) reported 4 novel mutations (C24Y, K142M, G315X, W475X) in Chinese OCA1 patients and first reported two known mutations ( c.896G>A and c.230G>A) in Chinese OCA1 patients.
(5) Rooryck, et al (2008) reported 13 novel ones: three splice site mutations (c.1185 -1 G>T, c.1366 +1 G>A, c.1366 +3A>T), three nonsense mutation (S163X, E219X, K465X), three missense mutations (H19R, K33T, W400C), one frameshift (c.820 -1_820GA>TG, one deletion of three nucleotides (c.505_507delCAG), one deletion of the entire gene (11q14.3 deletion), and one deletion of a single exon (Exon 2 deletion).
(6) Gronskov, et al (2009) reported 8 novel mutations (D76E, A206T, Q255X, C276Y, R299C, M332I, V427F, L452V) in Danish OCA or AROA patients.
(7) Wei, et al (2010) reported 15 previously unreported alleles: p.C24R, p.W39C, p.W39R, p.R77G, p.C100F, p.C100W, p.M185V, p.H211R, p.R212T, p.Y235H, p.W236R, p.D249G, c.1146C>G (p.N382K), p.A481E, and p.G506X in Chinese OCA patients. Interestingly, c.575C>A (p.S192Y) has been reported as a single-nucleotide polymorphism (SNP), rs1042602, in several populations. However, the A allele was not found in any of the 100 unaffected subjects from the Chinese Han population. Two alleles, p.R299H and c.929insC, are the most common alleles in Chinese OCA1 patients, accounting for 15.4% and 14.8%, respectively. About 81% alleles were clustered on exons 1 and 2 of TYR gene in this population.
Note that the 3' region (about 68 kb) of TYR, encompassing exons 4 and 5, has 98.55% sequence identity with a pseudogene (TYRL, 11p11.2, OMIM 191270). A PCR strategy to amplify TYR and TYRL separately was developed by Chaki et al. (2005). They found that the previously reported mutational allele c.1217C4T (p.P406L) was identified as an allele from the pseudogene, TYRL.
The majority of TYR mutations are missense or nonsense mutations. A large number of mutations have been identified in tyrosinase, with many leading to its misfolding, endoplasmic reticulum (ER) retention, and degradation. Many of the missense mutations are clustered in or flank the copper binding sites by affecting copper binding or by disrupting the substrate binding site (Spritz, et al). The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence (Oetting, et al).
Defects in TYR (OMIM 606933) are the cause of oculocutaneous albinism type IA (OCA-IA) (OMIM 203100), also known as oculocutaneous albinism type I (OCA-I). OCA-IA patients have no melanin synthesis with white skin and hair. In oculocutaneous albinism, the reduction in melanin pigment in the skin results in an increased sensitivity to ultraviolet radiation and to predisposition to skin cancer.
Defects in TYR are the cause of oculocutaneous albinism type IB (OCA-IB) (OMIM 606952), also known as albinism yellow mutant type. OCA-IB patients have white hair at birth that rapidly turns yellow or blond.
Defects in TYR are the cause of oculocutaneous albinism type I temperature sensitive (OCA-ITS) (OMIM 606952). OCA-ITS patients have white axilary and scalp hair and pigmented arm and leg hair.
Individuals with OCA1 show a complete absence of pigment in their skin, eyes and hair; this persists throughout life in the subtype OCA1A, whereas patients with subtype OCA1B have some residual tyrosinase activity and thus gradually accumulate minor amounts of pigment in their tissues.
Compound heterozygosity for the R402Q polymorphism and a mutant allele of TYR is a common cause of autosomal recessive ocular albinism. The R402Q polymorphism is also found in Waardenburg syndrome type II with ocular albinism (WS2-OA, OMIM 103470) in association with a deletion in the MITF gene.