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.
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.
The Kringle-like domain (KLD) contains six highly conserved cysteine residues that are critical for dimer formation.
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.
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.
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.
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).
Belongs to the PMEL/NMB family.
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.
D12S53E, PMEL17, SILV, PMEL, Melanocyte protein PMEL, ME20-M, Melanocyte protein Pmel 17, Melanocytes lineage-specific antigen GP100, Melanoma-associated ME20 antigen, P1, P100, Premelanosome protein, Silver locus protein homolog, ME20M
Proteins
Immunology & Infectious Disease
70255Da
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