PMEL (premelanosome protein, Pmel17, gp100, ME20, silver) is a pigment cell-specific single-pass type I membrane glycoprotein that forms the functional amyloid fibrils of melanosomes. It is synthesized in the ER as a disulfide-linked dimer, glycosylated in the Golgi, briefly reaches the cell surface and is delivered via endocytosis to multivesicular early (stage I) melanosomes, where it is sorted onto intraluminal vesicles with the help of CD63 and ApoE. Sequential cleavage by proprotein convertase, ADAM/BACE2 at the juxtamembrane site and gamma-secretase releases luminal fragments whose repeat (RPT) domain assembles at acidic pH into parallel amyloid sheets that elongate the organelle into a striated stage II premelanosome and serve as a scaffold on which eumelanin is deposited. PMEL is also a major melanoma-specific antigen (gp100) recognized by cytotoxic T cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001654 eye development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Eye development transferred from mouse Pmel. Reason: Pmel mutations affect pigmentation of ocular tissues (RPE, iris); any eye phenotype is a downstream consequence of melanosome biogenesis. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. |
| GO:0005515 protein binding | IPI PMID:15695812 MART-1 is required for the function of the melanosomal matri... | REMOVE | Summary: PMEL forms a complex with MART-1/MLANA. Reason: Bare protein binding is uninformative; MART-1 regulates PMEL stability, trafficking and processing, but no specific PMEL molecular function follows from the interaction. Supporting Evidence: PMID:15695812 We show that MART-1 forms a complex with Pmel17 and affects its expression, stability, trafficking, and the processing which is required for melanosome structure and maturation. |
| GO:0005515 protein binding | IPI PMID:20374249 The pathogenic E. coli type III effector EspZ interacts with... | REMOVE | Summary: PMEL recovered in a study of the E. coli effector EspZ. Reason: Bare protein binding with a bacterial effector from an interaction screen whose focus was CD98; uninformative and of no evident physiological relevance to PMEL function. Supporting Evidence: PMID:20374249 Using yeast two-hybrid, proteomics, immunofluorescence and co-immunoprecipitation, it was demonstrated that EspZ interacts with the host protein CD98 |
| GO:0005515 protein binding | IPI PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome... | REMOVE | Summary: PMEL associates with ApoE on intraluminal vesicles. Reason: Bare protein binding is uninformative; the biologically relevant point (ApoE-dependent sorting of PMEL onto ILVs for amyloid nucleation) is captured by melanosome organization and MVB internal vesicle annotations. Supporting Evidence: PMID:26387950 ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. |
| GO:0005576 extracellular region | EXP PMID:8179825 Cloning and expression of the gene for the melanoma-associat... | KEEP AS NON CORE | Summary: A soluble ME20-S form of PMEL is secreted by melanoma cells. Reason: A shed luminal fragment is released extracellularly, but PMEL functions inside melanosomes; the extracellular pool is secondary. Supporting Evidence: PMID:8179825 Human melanoma cells, but not tumor cells of other histological origin, express a unique membrane-associated glycoprotein, designated ME20-M, and secrete a soluble glycoprotein, designated ME20-S |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt Secreted mapping. Reason: As above. Supporting Evidence: PMID:8179825 Human melanoma cells, but not tumor cells of other histological origin, express a unique membrane-associated glycoprotein, designated ME20-M, and secrete a soluble glycoprotein, designated ME20-S |
| GO:0005771 multivesicular body | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt endosome/multivesicular body mapping. Reason: PMEL is sorted onto intraluminal vesicles of multivesicular bodies (stage I melanosomes), where fibrils nucleate. Supporting Evidence: PMID:11694580 In transfected nonpigmented cells Pmel17 associates with the intralumenal membrane vesicles of multivesicular bodies file:human/PMEL/PMEL-uniprot.txt Localizes predominantly to intralumenal vesicles (ILVs) within multivesicular bodies. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | MODIFY | Summary: HPA immunofluorescence ER. Reason: Correct but general; PMEL is a single-pass type I membrane protein in the ER membrane during biosynthesis (term already carried). Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:19047044 Formation of Pmel17 amyloid is regulated by juxtamembrane me... | KEEP AS NON CORE | Summary: PMEL is synthesized and dimerized in the ER membrane before trafficking. Reason: Correct biosynthetic location; a large steady-state pool resides in early biosynthetic compartments, but the functional site is the melanosome. Supporting Evidence: PMID:19047044 the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:15096515 Epitope mapping of the melanosomal matrix protein gp100 (PME... | KEEP AS NON CORE | Summary: PMEL is synthesized and dimerized in the ER membrane before trafficking. Reason: Correct biosynthetic location; a large steady-state pool resides in early biosynthetic compartments, but the functional site is the melanosome. Supporting Evidence: PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:15695812 MART-1 is required for the function of the melanosomal matri... | KEEP AS NON CORE | Summary: PMEL is synthesized and dimerized in the ER membrane before trafficking. Reason: Correct biosynthetic location; a large steady-state pool resides in early biosynthetic compartments, but the functional site is the melanosome. Supporting Evidence: PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: PMEL is synthesized and dimerized in the ER membrane before trafficking. Reason: Correct biosynthetic location; a large steady-state pool resides in early biosynthetic compartments, but the functional site is the melanosome. Supporting Evidence: PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence Golgi. Reason: PMEL transits the Golgi where it is O-glycosylated; biosynthetic transit location. Supporting Evidence: PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes |
| GO:0005794 Golgi apparatus | IDA PMID:15695812 MART-1 is required for the function of the melanosomal matri... | KEEP AS NON CORE | Summary: PMEL trafficking through Golgi in MART-1 study. Reason: Transit location. Supporting Evidence: PMID:15695812 We show that MART-1 forms a complex with Pmel17 and affects its expression, stability, trafficking, and the processing which is required for melanosome structure and maturation. PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt Golgi mapping. Reason: Transit location. Supporting Evidence: PMID:17991747 Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Plasma membrane inherited at family node. Reason: PMEL is only transiently present at the cell surface before endocytic delivery to early melanosomes; the plasma membrane is not its functional site. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Transiently expressed at the cell surface before targeting to early melanosomes (PubMed:16760433, PubMed:30988362). |
| GO:0005886 plasma membrane | TAS PMID:8179825 Cloning and expression of the gene for the melanoma-associat... | KEEP AS NON CORE | Summary: Plasma membrane from cloning of the ME20 antigen. Reason: The membrane-associated ME20-M form exists, and PMEL passes transiently through the plasma membrane, but steady-state localization is predominantly intracellular (ER, MVB/melanosomes). Supporting Evidence: PMID:8179825 Human melanoma cells, but not tumor cells of other histological origin, express a unique membrane-associated glycoprotein, designated ME20-M, and secrete a soluble glycoprotein, designated ME20-S file:human/PMEL/PMEL-uniprot.txt Transiently expressed at the cell surface before targeting to early melanosomes (PubMed:16760433, PubMed:30988362). |
| GO:0032438 melanosome organization | IBA GO_REF:0000033 | ACCEPT | Summary: Melanosome organization inherited. Reason: Core process: PMEL amyloid fibrils shape stage II premelanosomes. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. PMID:11694580 These results suggest that Pmel17 is sufficient to drive the formation of striations from within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes. |
| GO:0032438 melanosome organization | IDA PMID:11694580 Pmel17 initiates premelanosome morphogenesis within multives... | ACCEPT | Summary: Pmel17 drives formation of premelanosome striations within MVBs. Reason: Core process. Supporting Evidence: PMID:11694580 These results suggest that Pmel17 is sufficient to drive the formation of striations from within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes. |
| GO:0032585 multivesicular body membrane | IDA PMID:11694580 Pmel17 initiates premelanosome morphogenesis within multives... | ACCEPT | Summary: Pmel17 associates with intralumenal membrane vesicles of MVBs. Reason: Direct evidence; MVB/stage I melanosome membranes are where PMEL is sorted before fibril formation. Supporting Evidence: PMID:11694580 In transfected nonpigmented cells Pmel17 associates with the intralumenal membrane vesicles of multivesicular bodies |
| GO:0033106 cis-Golgi network membrane | IDA PMID:15096515 Epitope mapping of the melanosomal matrix protein gp100 (PME... | KEEP AS NON CORE | Summary: Rapid processing in the cis-Golgi. Reason: Biosynthetic transit compartment. Supporting Evidence: PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0033162 melanosome membrane | IDA PMID:15096515 Epitope mapping of the melanosomal matrix protein gp100 (PME... | ACCEPT | Summary: Epitope mapping localizes PMEL to immature melanosome membranes. Reason: The integral membrane form resides in melanosome precursor membranes where it is cleaved to release the luminal domain. Supporting Evidence: PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi PMID:23754390 BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis |
| GO:0033162 melanosome membrane | IDA PMID:23754390 BACE2 processes PMEL to form the melanosome amyloid matrix i... | ACCEPT | Summary: BACE2 cleaves membrane-bound PMEL in melanosome precursors. Reason: Direct evidence. Supporting Evidence: PMID:23754390 BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis |
| GO:0033162 melanosome membrane | TAS Reactome:R-HSA-9825846 | ACCEPT | Summary: Reactome places PMEL in melanosome membrane. Reason: Consistent with experimental data. Supporting Evidence: Reactome:R-HSA-9825846 PMID:23754390 BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis |
| GO:0042470 melanosome | EXP PMID:11694580 Pmel17 initiates premelanosome morphogenesis within multives... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: PMID:11694580 These results suggest that Pmel17 is sufficient to drive the formation of striations from within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes. |
| GO:0042470 melanosome | EXP PMID:12643545 Proteomic analysis of early melanosomes: identification of n... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. |
| GO:0042470 melanosome | EXP PMID:15096515 Epitope mapping of the melanosomal matrix protein gp100 (PME... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: PMID:15096515 is predominantly delivered directly to immature melanosomes following its rapid processing in the endoplasmic reticulum and cis-Golgi |
| GO:0042470 melanosome | EXP PMID:17081065 Proteomic and bioinformatic characterization of the biogenes... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. |
| GO:0042470 melanosome | EXP PMID:17991747 Premelanosome amyloid-like fibrils are composed of only golg... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: PMID:17991747 antibodies that detect Pmel17 within fibrillar melanosomes recognize only the luminal products of proprotein convertase cleavage |
| GO:0042470 melanosome | EXP PMID:23754390 BACE2 processes PMEL to form the melanosome amyloid matrix i... | ACCEPT | Summary: PMEL detected in melanosomes/premelanosomes. Reason: Core location: PMEL fibrils form the melanosome matrix. Supporting Evidence: PMID:23754390 BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis |
| GO:0042470 melanosome | IBA GO_REF:0000033 | ACCEPT | Summary: Melanosome inherited. Reason: Core location. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. |
| GO:0042470 melanosome | IDA PMID:15695812 MART-1 is required for the function of the melanosomal matri... | ACCEPT | Summary: PMEL in melanosomes (MART-1 study). Reason: Core location. Supporting Evidence: PMID:15695812 We show that MART-1 forms a complex with Pmel17 and affects its expression, stability, trafficking, and the processing which is required for melanosome structure and maturation. |
| GO:0042470 melanosome | IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome... | ACCEPT | Summary: PMEL fibrils in endosomes/melanosomes (ApoE study). Reason: Core location. Supporting Evidence: PMID:26387950 ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. |
| GO:0042470 melanosome | IEA GO_REF:0000120 | ACCEPT | Summary: Automated melanosome mapping. Reason: Core location. Supporting Evidence: file:human/PMEL/PMEL-uniprot.txt Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. |
| GO:0042802 identical protein binding | IPI PMID:19666488 The repeat domain of the melanosome fibril protein Pmel17 fo... | KEEP AS NON CORE | Summary: The PMEL RPT domain self-assembles into amyloid fibrils. Reason: Self-association is real and underlies functional amyloid formation; the more informative description is the amyloid fibril formation process and its structural role (proposed as NEW). Supporting Evidence: PMID:19666488 We show that this RPT region readily forms amyloid in vitro, but only under the mildly acidic conditions typical of the lysosome-like melanosome lumen |
| GO:0048023 positive regulation of melanin biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of melanin biosynthesis transferred from mouse. Reason: PMEL fibrils promote eumelanin polymerization and deposition; this is a scaffolding effect on pigment formation, downstream of its structural role. Supporting Evidence: PMID:19666488 Under the same mildly acidic conditions, the Pmel filaments promote eumelanin formation. file:human/PMEL/PMEL-uniprot.txt 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. |
| GO:0070062 extracellular exosome | IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome... | KEEP AS NON CORE | Summary: PMEL luminal fragments on ILVs secreted as exosomes. Reason: A minor secreted pool of ILV-associated PMEL; not its functional site. Supporting Evidence: PMID:26387950 ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes. PMID:26387950 ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. |
| GO:0097487 multivesicular body, internal vesicle | IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome... | ACCEPT | Summary: PMEL sorted onto MVB intraluminal vesicles in an ApoE-dependent manner. Reason: Direct evidence of the site of fibril nucleation. Supporting Evidence: PMID:26387950 ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. |
| GO:1903561 extracellular vesicle | EXP PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome... | MODIFY | Summary: Extracellular vesicles containing PMEL. Reason: Correct but general; the vesicles are exosomes derived from ILVs (extracellular exosome, already carried). Proposed replacements: extracellular exosome Supporting Evidence: PMID:26387950 ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes. |
| GO:1903561 extracellular vesicle | IEA GO_REF:0000044 | MODIFY | Summary: UniProt Extracellular vesicle mapping. Reason: As above. Proposed replacements: extracellular exosome Supporting Evidence: PMID:26387950 ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes. |
| GO:0005198 structural molecule activity | IDA PMID:11694580 Pmel17 initiates premelanosome morphogenesis within multives... | NEW | Summary: PMEL-derived fibrils form the structural matrix (striations) of premelanosomes. Reason: PMEL has no catalytic activity; its function is to build the amyloid matrix that gives melanosomes their shape and acts as the melanin deposition platform. Supporting Evidence: PMID:11694580 These results suggest that Pmel17 is sufficient to drive the formation of striations from within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes. file:human/PMEL/PMEL-uniprot.txt 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. |
| GO:1990000 amyloid fibril formation | IDA PMID:19666488 The repeat domain of the melanosome fibril protein Pmel17 fo... | NEW | Summary: The PMEL RPT domain forms amyloid at melanosomal pH. Reason: PMEL itself is the polymerizing subunit of the functional amyloid, so it performs the process rather than merely being required for it. Supporting Evidence: PMID:19666488 We show that this RPT region readily forms amyloid in vitro, but only under the mildly acidic conditions typical of the lysosome-like melanosome lumen PMID:19047044 the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position |
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Download this section (compressed HTML)Q: What fraction of PMEL reaches the plasma membrane in human melanocytes before endocytosis, and is surface transit obligatory for melanosome delivery?
Q: How do PMEL fibrils avoid forming toxic prefibrillar oligomers, and what role does the CAF/NTR domain play in nucleation?
Experiment: Surface biotinylation and antibody-feeding assays in human melanocytes to quantify the transient cell-surface pool of PMEL relative to direct Golgi-to-endosome delivery, with dynamin or AP-2 inhibition.
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