chain
-
signal peptide:1-24
-
chain:25-661
-
chain:25-467
-
chain:470-661
checksum
8A904FAB16715653
comment
-
FUNCTION Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. The maturation of unpigmented premelanosomes from stage I to II is marked by assembly of processed amyloidogenic fragments into parallel fibrillar sheets, which elongate the vesicle into a striated ellipsoidal shape. In pigmented stage III and IV melanosomes, the amyloid matrix serves as a platform where eumelanin precursors accumulate at high local concentrations for pigment formation. May prevent pigmentation-associated toxicity by sequestering toxic reaction intermediates of eumelanin biosynthesis pathway.FUNCTION Represents a potent melanoma-specific antigen. Among melanoma non-mutated self-peptides, G9-154 (KTWGQYWQV), G9-209 (ITDQVPFSV) and G9-280 (YLEPGPVTA), appear to act as immunodominant common epitopes that stimulate anti-tumor immune response mediated by HLA-A-restricted cytotoxic T cells.SUBUNIT Homodimer; disulfide-linked. Dimerization in the endoplasmic reticulum and early Golgi prevents premature fibril formation. The dimers are resolved to monomers in late- or post-Golgi compartments (PubMed:26694611). Heterooligomer; amyloid-type. Processed amyloidogenic fragments assemble into fibrils that further organize into beta-sheet quaternary amyloid structures (PubMed:28272432, PubMed:30988362). Interacts (via luminal C-terminal fragment) with CD63; this is important for sorting of the luminal fragment in tetraspanin rich microdomains in stage I melanosomes to prevent premature lysosomal degradation (PubMed:21962903). Interacts with APOE; this allows the loading of the luminal fragment on ILVs to induce fibril nucleation (PubMed:26387950). Interacts with MLANA (PubMed:15695812).INTERACTION Identified by mass spectrometry in melanosome fractions from stage I to stage IV (PubMed:17081065). Localizes predominantly to intralumenal vesicles (ILVs) within multivesicular bodies. Associates with ILVs found within the lumen of premelanosomes and melanosomes and particularly in compartments that serve as precursors to the striated stage II premelanosomes (PubMed:11694580, PubMed:12643545). Sorted to stage I melanosomes following its processing in the ER and cis-Golgi (PubMed:15096515). Transiently expressed at the cell surface before targeting to early melanosomes (PubMed:16760433, PubMed:30988362). Colocalizes with BACE2 in stage I and II melanosomes (PubMed:23754390). Colocalizes with CD63 and APOE at exosomes and in intraluminal vesicles within multivesicular endosomes (PubMed:21962903, PubMed:26387950).ALTERNATIVE PRODUCTS Normally expressed at low levels in quiescent adult melanocytes but overexpressed by proliferating neonatal melanocytes and during tumor growth. Overexpressed in melanomas. Some expression was found in dysplastic nevi.DOMAIN The core amyloid fragment (CAF) represents the amyloidogenic unit of melanosomal fibrils. It is predicted to form a beta-solenoid structure comprising four coil right-handed beta strands with Tyr-151 and Trp-160 residues pi-stacking against each other to confer stability.DOMAIN The highly O-glycosylated repeat (RPT) domain drives the generation of the fibrillar amyloid sheet structures within melanosomes. The O-glycosylation sites rather than its primary amino acid sequence are conserved across species.DOMAIN The Kringle-like domain (KLD) contains six highly conserved cysteine residues that are critical for dimer formation.PTM N- and O-glycosylated. A small amount of P1/P100 (major form) undergoes glycosylation in ER and Golgi compartments to yield P2/P120 (minor form). The mature P2 form leaves the trans-Golgi network and is mainly targeted to stage I melanosomes via the plasma membrane and clathrin-mediated endocytosis. Stage II melanosomes harbor only Golgi-modified fragments that are derived from M-alpha and that bear sialylated O-linked oligosaccharides. O-glycosylation of the RPT region is a conserved feature likely involved in amyloid sheet separation via electrostatic repulsion.PTM Undergoes multiple proteolytic processing. In a post-Golgi prelysosomal compartment, P2 is cleaved by a furin-like proprotein convertase (PC) into two disulfide-linked subunits: a large lumenal subunit, M-alpha/ME20-S, and an integral membrane subunit, M-beta. Despite cleavage, only a small fraction of M-alpha is secreted, as most M-alpha and M-beta remain associated with each other intracellularly via a disulfide bond (PubMed:11694580, PubMed:12732614, PubMed:15096515, PubMed:15695812, PubMed:17991747). Once targeted to stage I melanosomes, beta-secretase BACE2 cleaves the M-beta fragment to release the amyloidogenic luminal fragment containing M-alpha and a small portion of M-beta N-terminus (PubMed:23754390). M-alpha is further cleaved by metalloproteinases, likely ADAM10 or ADAM17, and still unknown proteases to yield subfragments that ultimately assemble into amyloid fibrils (PubMed:19047044). The C-terminal fragment of M-beta is processed by the gamma-secretase complex to release a short intracytoplasmic domain (PubMed:19047044).SIMILARITY Belongs to the PMEL/NMB family.SEQUENCE CAUTION Truncated N-terminus.
databaseName
UniProt
dbId
61870
description
-
recommendedName: Melanocyte protein PMEL alternativeName: ME20-M shortName: ME20M alternativeName: Melanocyte protein Pmel 17 alternativeName: Melanocytes lineage-specific antigen GP100 alternativeName: Melanoma-associated ME20 antigen alternativeName: P1 alternativeName: P100 alternativeName: Premelanosome protein alternativeName: Silver locus protein homolog component recommendedName: M-alpha alternativeName: 95 kDa melanocyte-specific secreted glycoprotein alternativeName: P26 alternativeName: Secreted melanoma-associated ME20 antigen shortName: ME20-S shortName: ME20S /component component recommendedName: M-beta /component
displayName
UniProt:P40967 PMEL
identifier
P40967
isSequenceChanged
false
keyword
-
3D-structure
-
Alternative splicing
-
Cleavage on pair of basic residues
-
Direct protein sequencing
-
Disulfide bond
-
Endoplasmic reticulum
-
Endosome
-
Glycoprotein
-
Golgi apparatus
-
Melanin biosynthesis
-
Membrane
-
Proteomics identification
-
Reference proteome
-
Repeat
-
Secreted
-
Sialic acid
-
Signal
-
Transmembrane
-
Transmembrane helix
moleculeType
Protein
otherIdentifier
-
11757418_a_at
-
16765845
-
16765848
-
209848_PM_s_at
-
209848_s_at
-
3457335
-
3457337
-
3457338
-
3457339
-
3457340
-
3457341
-
3457342
-
3457343
-
3457344
-
3457345
-
3457346
-
3457347
-
3457348
-
3457349
-
3457350
-
3457351
-
3457352
-
3457353
-
3457354
-
3457355
-
3457356
-
3457357
-
3457358
-
3457359
-
3457360
-
3457361
-
3457362
-
3457363
-
3457369
-
38327_at
-
6490
-
7963970
-
A_23_P312851
-
GE79639
-
GO:0005515
-
GO:0005576
-
GO:0005768
-
GO:0005771
-
GO:0005783
-
GO:0005789
-
GO:0005794
-
GO:0005886
-
GO:0016020
-
GO:0031410
-
GO:0032438
-
GO:0032585
-
GO:0033106
-
GO:0033162
-
GO:0042438
-
GO:0042470
-
GO:0042802
-
GO:0048023
-
GO:0070062
-
GO:0097487
-
HMNXSV003015530
-
HMNXSV003027108
-
HMNXSV003035354
-
ILMN_1665994
-
M77348_rna1_s_at
-
PH_hs_0005222
-
TC12001589.hg
-
TC12001590.hg
-
U31799_at
-
g494939_3p_a_at
schemaClass
ReferenceGeneProduct
secondaryIdentifier
-
PMEL_HUMAN
-
B3KS57
-
B7Z6D7
-
Q12763
-
Q14448
-
Q14817
-
Q16565
sequenceLength
661
stId
uniprot:P40967