TYRP1 (tyrosinase-related protein 1, gp75) is a single-pass type I membrane glycoprotein of melanocytes and pigmented epithelia, and the most abundant protein of the melanosome membrane. Its large lumenal domain contains a cysteine-rich EGF-like subdomain and a tyrosinase-like subdomain with a binuclear metal site, while its short cytoplasmic tail carries sorting signals, including a C-terminal PDZ-binding motif recognized by GIPC and an AP-1-dependent signal, that route the protein from the Golgi through endosomes to maturing melanosomes. TYRP1 is required for normal eumelanin synthesis and influences the type of melanin produced; mouse Tyrp1 oxidizes DHICA, whereas purified human TYRP1 binds zinc and shows this activity only after copper substitution, so whether the human protein is catalytic or acts mainly by stabilizing tyrosinase remains unsettled. Biallelic loss-of-function variants cause oculocutaneous albinism type 3. In melanoma cells a minor pool of TYRP1 is exposed at the plasma membrane, which is why it is used as an antibody and CAR-T target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001654 eye development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred eye development. Reason: Loss of TYRP1 reduces eye pigmentation (OCA3) but TYRP1 does not execute eye morphogenesis; the pigmentation aspect is captured by eye pigmentation. Supporting Evidence: PMID:21996312 autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye |
| GO:0004097 catechol oxidase activity | TAS Reactome:R-HSA-8878581 | KEEP AS NON CORE | Summary: Reactome describes TYRP1 as a DHICA oxidase (oxidation of DHICA to IQCA). Reason: Purified human TYRP1 contains zinc and lacks DHICA oxidase activity, which appears only after copper substitution; the native activity in melanosomes remains disputed. Retained as a possible, non-core activity rather than removed. Supporting Evidence: Reactome:R-HSA-8878581 PMID:28661582 We show that the active site contains two zinc ions, rather than copper ions as in tyrosinases, which makes it unlikely that human TYRP1 is a redox enzyme PMID:28661582 exchanging the Zn2+/Cu2+ cofactors of TYRP1/TYR for Cu2+/Zn2+ conferred |
| GO:0004503 tyrosinase activity | IBA GO_REF:0000033 | REMOVE | Summary: PAINT propagation of tyrosinase activity across the tyrosinase family. Reason: TYRP1 has diverged from TYR: its binuclear site binds zinc and the purified lumenal domain lacks tyrosine hydroxylase and L-DOPA oxidase activity. Tyrosinase activity is a TYR function not retained by TYRP1. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000895596 SOURCE BAD The ancestral node places tyrosinase activity across the family, but the TYRP1 subfamily has diverged: the human protein binds zinc rather than copper and the purified lumenal domain shows no tyrosine hydroxylase or L-DOPA oxidase activity. Supporting Evidence: PMID:28661582 We show that the active site contains two zinc ions, rather than copper ions as in tyrosinases, which makes it unlikely that human TYRP1 is a redox enzyme PMID:28661582 the intramelanosomal domain of TYRP1 did not display any DHICA activity nor tyrosine hydroxylase or l |
| GO:0004503 tyrosinase activity | IDA PMID:21291857 Interactions between GIPC-APPL and GIPC-TRP1 regulate melano... | REMOVE | Summary: IDA tyrosinase activity from a GIPC/APPL knockdown study. Reason: The cited full text measures total cellular tyrosinase activity in melanocyte lysates, reflecting TYR protein levels rather than an activity of TYRP1; purified human TYRP1 lacks tyrosinase activity. Supporting Evidence: PMID:21291857 western blot analysis showed reduced tyrosinase protein and enzyme assays showed tyrosinase activity in GIPC and APPL-knockdown cells PMID:28661582 the intramelanosomal domain of TYRP1 did not display any DHICA activity nor tyrosine hydroxylase or l |
| GO:0005515 protein binding | IPI PMID:11441007 PDZ domain protein GIPC interacts with the cytoplasmic tail ... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0005515 protein binding | IPI PMID:19841138 AP-1 and KIF13A coordinate endosomal sorting and positioning... | REMOVE | Summary: Bare protein binding from an interaction assay. Reason: Generic protein binding is uninformative under the protein-binding policy; the interaction is not disputed but no more specific function is established by this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21291857 Interactions between GIPC-APPL and GIPC-TRP1 regulate melano... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein binding from an interaction assay. Reason: Generic protein binding is uninformative under the protein-binding policy; the interaction is not disputed but no more specific function is established by this row. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Interaction of the TYRP1 C-terminal PDZ-binding motif with PDZ-domain proteins. Reason: The informative activity is PDZ domain binding: the TYRP1 C-terminal Ser-Val-Val motif binds PDZ domains (GIPC and others), mediating biosynthetic sorting toward melanosomes. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11441007 Carboxyl-terminal amino acid residues, Ser-Val-Val, of gp75 are necessary and sufficient for interaction of gp75 with the single PDZ domain in GIPC. PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ |
| GO:0005737 cytoplasm | IDA PMID:21291857 Interactions between GIPC-APPL and GIPC-TRP1 regulate melano... | MODIFY | Summary: TYRP1 detected in the cytoplasm (Golgi region and melanosomal compartments). Reason: Too general; TYRP1 is an integral membrane protein of the secretory/melanosomal pathway, specifically the melanosome membrane. Proposed replacements: melanosome membrane Supporting Evidence: PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0010008 endosome membrane | IDA PMID:19841138 AP-1 and KIF13A coordinate endosomal sorting and positioning... | KEEP AS NON CORE | Summary: TYRP1 transits endosomes en route to melanosomes. Reason: Correct trafficking-intermediate location; TYRP1 accumulates in vacuolar endosomes when AP-1 or KIF13A are depleted. Peripheral to its melanosomal function. Supporting Evidence: PMID:19841138 sequestration of melanosomal enzymes like Tyrp1 in vacuolar endosomes |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro oxidoreductase mapping from the tyrosinase-like domain. Reason: Correct but general; the specific (and disputed) activity proposed for TYRP1 is DHICA oxidation, captured by catechol oxidase activity (GO:0004097), already carried by the gene. Proposed replacements: catechol oxidase activity Supporting Evidence: PMID:28661582 exchanging the Zn2+/Cu2+ cofactors of TYRP1/TYR for Cu2+/Zn2+ conferred |
| GO:0030318 melanocyte differentiation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT inference of melanocyte differentiation. Reason: TYRP1 is a melanocyte differentiation marker and pigmentation protein, but there is no evidence it drives differentiation; OCA3 patients retain melanocytes. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002607660 SOURCE WEAK OR INFERRED Pigmentation phenotypes in family members are read as a role in melanocyte differentiation; TYRP1 is a differentiation marker and melanogenic protein rather than a driver of the differentiation program. Supporting Evidence: PMID:21996312 autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000117 | MODIFY | Summary: Electronic mapping to cytoplasmic vesicle membrane. Reason: Correct but general; melanosome membrane is the specific supported location. Proposed replacements: melanosome membrane Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0030669 clathrin-coated endocytic vesicle membrane | IDA PMID:19841138 AP-1 and KIF13A coordinate endosomal sorting and positioning... | KEEP AS NON CORE | Summary: TYRP1 found in clathrin-coated endocytic vesicle membranes. Reason: Consistent with a TYRP1 pool cycling through endosomes (and, in melanoma cells, the cell surface) before reaching melanosomes; a trafficking intermediate, not the functional site. Supporting Evidence: PMID:19841138 sequestration of melanosomal enzymes like Tyrp1 in vacuolar endosomes PMID:18334748 melanosomes and on the surface of melanoma cells |
| GO:0032438 melanosome organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of melanosome organization. Reason: TYRP1 contributes to melanosome maturation and stability, but this is secondary to its role in melanin synthesis. Supporting Evidence: PMID:19841138 sequestration of melanosomal enzymes like Tyrp1 in vacuolar endosomes |
| GO:0033162 melanosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TYRP1 is a type I membrane protein of the melanosome, with its catalytic-like domain in the lumen. Reason: Core location: TYRP1 is the most abundant melanosomal membrane protein. Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0033162 melanosome membrane | ISS GO_REF:0000024 | ACCEPT | Summary: TYRP1 is a type I membrane protein of the melanosome, with its catalytic-like domain in the lumen. Reason: Core location: TYRP1 is the most abundant melanosomal membrane protein. Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0033162 melanosome membrane | TAS Reactome:R-HSA-8878581 | ACCEPT | Summary: TYRP1 is a type I membrane protein of the melanosome, with its catalytic-like domain in the lumen. Reason: Core location: TYRP1 is the most abundant melanosomal membrane protein. Supporting Evidence: Reactome:R-HSA-8878581 Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0033162 melanosome membrane | TAS Reactome:R-HSA-9824593 | ACCEPT | Summary: TYRP1 is a type I membrane protein of the melanosome, with its catalytic-like domain in the lumen. Reason: Core location: TYRP1 is the most abundant melanosomal membrane protein. Supporting Evidence: Reactome:R-HSA-9824593 Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0042438 melanin biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Role in melanin biosynthesis. Reason: TYRP1 mutations cause OCA3 with reduced melanin synthesis; TYRP1 is a melanogenic protein of the melanosome membrane. Supporting Evidence: PMID:21996312 the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments PMID:28661582 the effect of mutations in the TYRP1 gene suggest the utmost importance of TYRP1 for the biosynthesis of melanin |
| GO:0042438 melanin biosynthetic process | TAS Reactome:R-HSA-5662702 | ACCEPT | Summary: Reactome melanin biosynthesis. Reason: Consistent with OCA3 genetics and the melanosomal location. Supporting Evidence: Reactome:R-HSA-5662702 PMID:21996312 the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments |
| GO:0042470 melanosome | IBA GO_REF:0000033 | MODIFY | Summary: TYRP1 localizes to melanosomes. Reason: Correct but general; TYRP1 is an integral (single-pass type I) membrane protein of melanosomes, so melanosome membrane (GO:0033162, already carried by the gene) is the supported term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002607660 SUPPORTS TRANSFER The ancestral node supports the location/function class, but the inherited term is broader than the specific term supported for this gene. Proposed replacements: melanosome membrane Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0042470 melanosome | IEA GO_REF:0000107 | MODIFY | Summary: TYRP1 localizes to melanosomes. Reason: Correct but general; TYRP1 is an integral (single-pass type I) membrane protein of melanosomes, so melanosome membrane (GO:0033162, already carried by the gene) is the supported term. Proposed replacements: melanosome membrane Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0042470 melanosome | ISS GO_REF:0000024 | MODIFY | Summary: TYRP1 localizes to melanosomes. Reason: Correct but general; TYRP1 is an integral (single-pass type I) membrane protein of melanosomes, so melanosome membrane (GO:0033162, already carried by the gene) is the supported term. Proposed replacements: melanosome membrane Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred identical protein binding. Reason: Structural and solution data describe human TYRP1 as a monomer; self-association is not established. Supporting Evidence: file:human/TYRP1/TYRP1-uniprot.txt Monomer (PubMed:28661582) |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred homodimerization activity. Reason: Human TYRP1 is reported as a monomer. Supporting Evidence: file:human/TYRP1/TYRP1-uniprot.txt Monomer (PubMed:28661582) |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS homodimerization activity. Reason: Human TYRP1 is reported as a monomer. Supporting Evidence: file:human/TYRP1/TYRP1-uniprot.txt Monomer (PubMed:28661582) |
| GO:0048023 positive regulation of melanin biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: TYRP1 promotes melanin synthesis. Reason: Supported by OCA3 genetics; because the mechanism (DHICA oxidation versus stabilization of tyrosinase) is unresolved, a positive-regulation term is appropriate. Supporting Evidence: PMID:21996312 the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments |
| GO:0048023 positive regulation of melanin biosynthetic process | IMP PMID:21996312 Oculocutaneous albinism type 3: a Japanese girl with novel m... | ACCEPT | Summary: An OCA3 mutant TYRP1 (p.C30R) cannot support melanin synthesis. Reason: Direct human mutant evidence. Supporting Evidence: PMID:21996312 the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments |
| GO:0048069 eye pigmentation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred eye pigmentation. Reason: OCA3 affects iris pigmentation; an organismal-level consequence of melanin synthesis. Supporting Evidence: PMID:21996312 autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye |
| GO:0097708 intracellular vesicle | IDA PMID:21291857 Interactions between GIPC-APPL and GIPC-TRP1 regulate melano... | MODIFY | Summary: TYRP1 detected in intracellular vesicles. Reason: Correct but general; melanosome membrane is the specific supported location. Proposed replacements: melanosome membrane Supporting Evidence: PMID:21291857 GIPC interacts with newly synthesized melanosomal protein TRP1 in the Golgi region Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0098588 bounding membrane of organelle | IEA GO_REF:0000117 | MODIFY | Summary: Electronic mapping to bounding membrane of organelle. Reason: Correct but general; melanosome membrane is the specific supported location. Proposed replacements: melanosome membrane Supporting Evidence: Reactome:R-HSA-8878581 is an abundant protein in the melanosome membrane |
| GO:0009986 cell surface | IDA PMID:18334748 Generation and characterization of a therapeutic human antib... | NEW | Summary: A minor pool of TYRP1 reaches the cell surface of melanoma cells, where its lumenal (then extracellular-facing) domain is bound by antibodies in flow cytometry and exploited therapeutically. Reason: Cell surface is absent from GOA for TYRP1. Flow cytometry with anti-TYRP1 antibodies on native melanoma cells, and surface-directed antibody and CAR-T targeting, support an accessible surface pool; it is minor and non-core relative to the melanosome membrane, and consistent with the endosomal cycling documented for TYRP1. Supporting Evidence: PMID:18334748 melanosomes and on the surface of melanoma cells PMID:18334748 native TYRP1 in melanoma cells as determined by flow cytometry analysis PMID:39308793 We next assessed TYRP1 surface expression on several human and mouse melanoma cell lines demonstrating detectable TYRP1 on a subset of melanoma cell lines |
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Download this section (compressed HTML)Q: Does melanosomal TYRP1 acquire copper in vivo (for example through ATP7A) and thereby function as a genuine DHICA oxidase, or is its contribution to pigmentation structural?
Q: What fraction of TYRP1 reaches the plasma membrane in normal melanocytes versus melanoma cells, and what trafficking step determines this?
Experiment: Measure metal content and DHICA oxidase activity of TYRP1 immunopurified from human melanosomes (rather than from insect-cell expression) to settle the native cofactor and activity.
Experiment: Quantify surface versus melanosomal TYRP1 by surface biotinylation and antibody binding in primary melanocytes and matched melanoma lines, testing dependence on AP-1 and the cytoplasmic sorting motifs.
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