Vacuolar protein sorting-associated protein 35 (VPS35) is the central alpha-helical solenoid scaffold of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29) on endosomal membranes. Its N-terminal region binds the arrestin-like subunit VPS26A or VPS26B and cooperates with SNX3 to couple recognition of canonical omega-Phi-[L/M] sorting motifs in transmembrane cargoes to endosomal membrane recruitment, while its C-terminal sickle-shaped solenoid wraps around VPS29, forms the antiparallel homodimeric legs of membrane-assembled retromer arches, and recruits the WASH complex (via FAM21) to coordinate endosome-to-trans-Golgi network retrograde retrieval and SNX27-dependent endosome-to-plasma-membrane recycling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:16732284 The retromer subunit Vps26 has an arrestin fold and binds Vp... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:17616579 Cellular cofactors affecting hepatitis C virus infection and... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:17891154 Functional architecture of the retromer cargo-recognition co... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:17891154 Functional architecture of the retromer cargo-recognition co... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:18160348 The retromer complex influences Wnt secretion by recycling w... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:19553991 GOLPH3 modulates mTOR signalling and rapamycin sensitivity i... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:19619496 The retromer coat complex coordinates endosomal sorting and ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:19619496 The retromer coat complex coordinates endosomal sorting and ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:20923837 The cargo-selective retromer complex is a recruiting hub for... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:20923837 The cargo-selective retromer complex is a recruiting hub for... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:21725319 A SNX3-dependent retromer pathway mediates retrograde transp... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:22719997 SNX12 role in endosome membrane transport. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:22719997 SNX12 role in endosome membrane transport. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:22719997 SNX12 role in endosome membrane transport. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:23331060 Endosomal recruitment of the WASH complex: active sequences ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:23331060 Endosomal recruitment of the WASH complex: active sequences ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:23331060 Endosomal recruitment of the WASH complex: active sequences ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:23331060 Endosomal recruitment of the WASH complex: active sequences ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:23452853 Regulation of WASH-dependent actin polymerization and protei... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24152121 The Vps35 D620N mutation linked to Parkinson's disease disru... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24152121 The Vps35 D620N mutation linked to Parkinson's disease disru... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24152121 The Vps35 D620N mutation linked to Parkinson's disease disru... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24344282 A mechanism for retromer endosomal coat complex assembly wit... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24344282 A mechanism for retromer endosomal coat complex assembly wit... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24747528 Pharmacological chaperones stabilize retromer to limit APP p... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24747528 Pharmacological chaperones stabilize retromer to limit APP p... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24980502 Retromer binding to FAM21 and the WASH complex is perturbed ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24980502 Retromer binding to FAM21 and the WASH complex is perturbed ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24980502 Retromer binding to FAM21 and the WASH complex is perturbed ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24980502 Retromer binding to FAM21 and the WASH complex is perturbed ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:24980502 Retromer binding to FAM21 and the WASH complex is perturbed ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:25278552 Identification of molecular heterogeneity in SNX27-retromer-... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:25278552 Identification of molecular heterogeneity in SNX27-retromer-... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27460146 VPS35 regulates cell surface recycling and signaling of dopa... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:27460146 VPS35 regulates cell surface recycling and signaling of dopa... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:28892079 Retriever is a multiprotein complex for retromer-independent... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:30213940 SNX3-retromer requires an evolutionary conserved MON2:DOPEY2... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:37172566 Structure of the endosomal Commander complex linked to Ritsc... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:37172566 Structure of the endosomal Commander complex linked to Ritsc... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:37172566 Structure of the endosomal Commander complex linked to Ritsc... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Uninformative generic protein binding term removed per policy. Reason: Broad GO:0005515 protein binding annotation is removed as uninformative per the protein-binding policy; VPS35's assembly into the retromer cargo-selective complex and its cargo adaptor activity are captured by GO:0030906 and GO:0140312. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Cytoplasm localization is true but too general; refine to cytosol and endosome membrane. Reason: VPS35 cycles between a soluble cytosolic pool and the cytoplasmic face of endosomal membranes as part of the retromer complex; refine GO:0005737 (cytoplasm) to GO:0005829 (cytosol) and GO:0010008 (endosome membrane). Proposed replacements: cytosol endosome membrane Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. |
| GO:0005739 mitochondrion | IDA PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Secondary localization of VPS35 to mitochondria during DLP1 complex turnover and MDV budding. Reason: Wang et al. (PMID:26618722) demonstrated by confocal 3D reconstruction of endogenous VPS35 colocalizing with mitoDsRed2-labelled mitochondria (Fig. 5a, complementing biochemical fractionation in Fig. 5e and thus ruling out crude-fraction ER/MAM contamination) that a pool of VPS35 localizes to mitochondria and interacts with DLP1 to mediate mitochondria-derived vesicle (MDV) transport; retained on the root organelle term as KEEP_AS_NON_CORE relative to VPS35's primary endosomal retromer localization. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. PMID:26618722 M17 cells transfected with mitoDsRed2 and immunostained with antibodies against DLP1 and VPS35 were imaged and 3D reconstructed images demonstrated the colocalization of DLP1 puncta and VPS35 on mitochondria (Fig. 5a). |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: High-throughput proteomic detection of VPS35 on purified placental lysosomal membranes retained as non-core. Reason: Schroder et al. (PMID:17897319) detected VPS35 in membranes purified from human placental lysosomes; because retromer acts primarily on early and maturing endosomes to prevent cargo delivery to lysosomes, this late endolysosomal membrane pool is retained as non-core. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. ... We report on additional 86 proteins that were significantly enriched in the lysosomal membrane fraction. |
| GO:0005768 endosome | IDA GO_REF:0000052 | ACCEPT | Summary: VPS35 localizes to endosomes as the central scaffold of the retromer complex. Reason: Direct immunofluorescence, cryo-ET, and biochemical studies establish that VPS35 associates with endosomes to mediate transmembrane cargo sorting. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0005768 endosome | IDA GO_REF:0000054 | ACCEPT | Summary: VPS35 localizes to endosomes as the central scaffold of the retromer complex. Reason: Direct immunofluorescence, cryo-ET, and biochemical studies establish that VPS35 associates with endosomes to mediate transmembrane cargo sorting. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0005768 endosome | IDA PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | ACCEPT | Summary: VPS35 localizes to endosomes as the central scaffold of the retromer complex. Reason: Direct immunofluorescence, cryo-ET, and biochemical studies establish that VPS35 associates with endosomes to mediate transmembrane cargo sorting. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0005768 endosome | IDA PMID:28892079 Retriever is a multiprotein complex for retromer-independent... | ACCEPT | Summary: VPS35 localizes to endosomes as the central scaffold of the retromer complex. Reason: Direct immunofluorescence, cryo-ET, and biochemical studies establish that VPS35 associates with endosomes to mediate transmembrane cargo sorting. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0005768 endosome | IEA GO_REF:0000120 | ACCEPT | Summary: VPS35 localizes to endosomes as the central scaffold of the retromer complex. Reason: Direct immunofluorescence, cryo-ET, and biochemical studies establish that VPS35 associates with endosomes to mediate transmembrane cargo sorting. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0005769 early endosome | IDA PMID:18160348 The retromer complex influences Wnt secretion by recycling w... | ACCEPT | Summary: VPS35 localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Direct imaging studies show that VPS35 localizes to early endosomes and their tubular exit domains to retrieve CI-MPR, Wntless, and DMT1-II. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. |
| GO:0005769 early endosome | IDA PMID:20164305 Retromer-mediated direct sorting is required for proper endo... | ACCEPT | Summary: VPS35 localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Direct imaging studies show that VPS35 localizes to early endosomes and their tubular exit domains to retrieve CI-MPR, Wntless, and DMT1-II. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. |
| GO:0005769 early endosome | IDA PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS35 localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Direct imaging studies show that VPS35 localizes to early endosomes and their tubular exit domains to retrieve CI-MPR, Wntless, and DMT1-II. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. |
| GO:0005769 early endosome | IEA GO_REF:0000044 | ACCEPT | Summary: VPS35 localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Direct imaging studies show that VPS35 localizes to early endosomes and their tubular exit domains to retrieve CI-MPR, Wntless, and DMT1-II. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. |
| GO:0005770 late endosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Association of VPS35 with maturing/late endosomes during retrograde receptor retrieval retained as non-core. Reason: Immunoelectron microscopy (Arighi et al., PMID:15078903) shows that mammalian retromer associates with tubular-vesicular profiles emanating from early endosomes and from intermediates in early-to-late endosome maturation; retained as non-core relative to its primary early/tubular endosome membrane localization. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000120819 Β· VPS35 family node SUPPORTS TRANSFER Retromer remains associated with maturing early-to-late endosomes across eukaryotes. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. |
| GO:0005770 late endosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Association of VPS35 with maturing/late endosomes during retrograde receptor retrieval retained as non-core. Reason: Immunoelectron microscopy (Arighi et al., PMID:15078903) shows that mammalian retromer associates with tubular-vesicular profiles emanating from early endosomes and from intermediates in early-to-late endosome maturation; retained as non-core relative to its primary early/tubular endosome membrane localization. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. |
| GO:0005829 cytosol | IDA PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS35 exists in a soluble cytosolic pool that is dynamically recruited to endosomal membranes. Reason: Biochemical fractionation in PMID:11102511 and Reactome curation confirm that the VPS35-VPS26-VPS29 heterotrimer cycles between the cytosol and endosomal membranes. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247836 | ACCEPT | Summary: VPS35 exists in a soluble cytosolic pool that is dynamically recruited to endosomal membranes. Reason: Biochemical fractionation in PMID:11102511 and Reactome curation confirm that the VPS35-VPS26-VPS29 heterotrimer cycles between the cytosol and endosomal membranes. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247839 | ACCEPT | Summary: VPS35 exists in a soluble cytosolic pool that is dynamically recruited to endosomal membranes. Reason: Biochemical fractionation in PMID:11102511 and Reactome curation confirm that the VPS35-VPS26-VPS29 heterotrimer cycles between the cytosol and endosomal membranes. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247849 | ACCEPT | Summary: VPS35 exists in a soluble cytosolic pool that is dynamically recruited to endosomal membranes. Reason: Biochemical fractionation in PMID:11102511 and Reactome curation confirm that the VPS35-VPS26-VPS29 heterotrimer cycles between the cytosol and endosomal membranes. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. |
| GO:0007040 lysosome organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream requirement of VPS35-mediated CI-MPR retrieval for normal lysosome morphology and hydrolase content retained as non-core. Reason: Depletion or mutation of VPS35 causes lysosomal turnover of CI-MPR, reduced lysosomal hydrolases such as cathepsin D, and lysosomal swelling (Arighi et al., PMID:15078903; Follett et al., PMID:24152121); because lysosome organization is a downstream consequence of endosome-to-TGN hydrolase receptor retrieval, it is retained as non-core. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:24152121 While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of Ξ±-synuclein, a causative agent of PD. |
| GO:0009967 positive regulation of signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: Broad positive regulation of signal transduction annotation should be refined to specific retromer sorting pathways. Reason: GO:0009967 (positive regulation of signal transduction) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0010008 endosome membrane | IDA PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS35 is recruited to the cytoplasmic face of the endosome membrane. Reason: Structural and cell biological studies show that the VPS35-VPS26-VPS29 heterotrimer assembles on the cytoplasmic surface of the endosome membrane via sorting nexin complexes (SNX3 and Vps5/SNX-BAR arrays). Supporting Evidence: PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0010008 endosome membrane | NAS PMID:30072228 Endosomal Retrieval of Cargo: Retromer Is Not Alone. | ACCEPT | Summary: VPS35 is recruited to the cytoplasmic face of the endosome membrane. Reason: Structural and cell biological studies show that the VPS35-VPS26-VPS29 heterotrimer assembles on the cytoplasmic surface of the endosome membrane via sorting nexin complexes (SNX3 and Vps5/SNX-BAR arrays). Supporting Evidence: PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0010628 positive regulation of gene expression | IDA PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (positive regulation of gene expression) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute positive regulation of gene expression; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (positive regulation of gene expression) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute positive regulation of gene expression; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (negative regulation of gene expression) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute negative regulation of gene expression; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0010821 regulation of mitochondrion organization | IGI PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Role of VPS35 in regulating mitochondrial morphology via DLP1 complex turnover retained as non-core. Reason: Wang et al. (PMID:26618722) showed that VPS35 and VPS26 regulate mitochondrial aspect ratio and organization by clearing inhibitory oligomeric DLP1 complexes via mitochondria-derived vesicles; retained as a specialized non-core function. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to the postsynaptic density retained as non-core. Reason: In neurons, VPS35 localizes to dendritic spines and PSD95-positive postsynaptic compartments where it recycles neurotransmitter receptors and maintains spine morphology (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific subcompartment relative to universal endosomal membrane localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0015031 protein transport | IEA GO_REF:0000002 | MODIFY | Summary: Broad protein transport annotation should be refined to specific retromer sorting pathways. Reason: GO:0015031 (protein transport) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Generic membrane term should be refined to endosome membrane. Reason: GO:0016020 (membrane) is overly general; VPS35 is recruited to the cytoplasmic leaflet of the endosome membrane (GO:0010008) as the central scaffold of the retromer complex. Proposed replacements: endosome membrane Supporting Evidence: PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0016055 Wnt signaling pathway | NAS PMID:24115276 The regulation and deregulation of Wnt signaling by PARK gen... | KEEP AS NON CORE | Summary: Cargo-specific requirement of VPS35 retromer for Wntless retrieval and Wnt signaling retained as non-core. Reason: Retromer is required for Wnt signaling because it retrieves the Wnt sorting receptor Wntless (WLS) from endosomes to the TGN, preventing its lysosomal degradation (Belenkaya et al., PMID:18160348; Franch-Marro et al., PMID:18193037); retained as a cargo-specific downstream pathway. Supporting Evidence: PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. |
| GO:0016241 regulation of macroautophagy | TAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | KEEP AS NON CORE | Summary: Downstream role of retromer in maintaining autophagic flux via lysosomal hydrolase delivery retained as non-core. Reason: Maruzs et al. (PMID:26172538) showed that loss of Vps35/Vps26 impairs late stages of autophagy due to defective lysosomal degradation of autophagic cargo; retained as a downstream non-core consequence of retromer-dependent lysosomal maintenance. Supporting Evidence: PMID:26172538 Here we show that the late stages of autophagy and endocytosis are impaired in Vps26 and Vps35 deficient Drosophila larval fat body cells, but formation of autophagosomes and endosomes is not compromised. |
| GO:0030904 retromer complex | IBA GO_REF:0000033 | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000120819 Β· VPS35 family node SUPPORTS TRANSFER Conserved across all eukaryotic VPS35 orthologs. SGD:S000003690 Β· yeast VPS35 SUPPORTS TRANSFER Foundational yeast retromer Vps35 subunit. UniProtKB:Q96QK1 Β· human VPS35 SUPPORTS TRANSFER Direct experimental evidence in human. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | IDA PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | IDA PMID:28892079 Retriever is a multiprotein complex for retromer-independent... | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | IEA GO_REF:0000120 | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | NAS PMID:18193037 Wingless secretion requires endosome-to-Golgi retrieval of W... | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | TAS PMID:17239604 The vacuolar-ATPase inhibitor bafilomycin and mutant VPS35 i... | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030904 retromer complex | TAS PMID:24115276 The regulation and deregulation of Wnt signaling by PARK gen... | ACCEPT | Summary: VPS35 is the central alpha-helical solenoid subunit of the retromer complex. Reason: Cloning, co-immunoprecipitation, and structural studies establish VPS35 as the core scaffold of the retromer complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network |
| GO:0030906 retromer, cargo-selective complex | IDA PMID:20164305 Retromer-mediated direct sorting is required for proper endo... | ACCEPT | Summary: VPS35 forms the spine of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS35 binds VPS26A/B at its N-terminus and wraps around VPS29 at its C-terminus to form the heterotrimeric retromer cargo-selective complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0030906 retromer, cargo-selective complex | IDA PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS35 forms the spine of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS35 binds VPS26A/B at its N-terminus and wraps around VPS29 at its C-terminus to form the heterotrimeric retromer cargo-selective complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0030906 retromer, cargo-selective complex | IEA GO_REF:0000002 | ACCEPT | Summary: VPS35 forms the spine of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS35 binds VPS26A/B at its N-terminus and wraps around VPS29 at its C-terminus to form the heterotrimeric retromer cargo-selective complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0030906 retromer, cargo-selective complex | IPI PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS35 forms the spine of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS35 binds VPS26A/B at its N-terminus and wraps around VPS29 at its C-terminus to form the heterotrimeric retromer cargo-selective complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0030906 retromer, cargo-selective complex | NAS PMID:26220253 Retromer: Structure, function, and roles in mammalian diseas... | ACCEPT | Summary: VPS35 forms the spine of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS35 binds VPS26A/B at its N-terminus and wraps around VPS29 at its C-terminus to form the heterotrimeric retromer cargo-selective complex. Supporting Evidence: PMID:11102511 We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. ... Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000117 | MODIFY | Summary: Broad regulation of protein stability annotation should be refined to specific retromer sorting pathways. Reason: GO:0031647 (regulation of protein stability) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0031647 regulation of protein stability | IMP PMID:18193037 Wingless secretion requires endosome-to-Golgi retrieval of W... | MODIFY | Summary: Broad regulation of protein stability annotation should be refined to specific retromer sorting pathways. Reason: GO:0031647 (regulation of protein stability) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0031648 protein destabilization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Indirect effect of VPS35-dependent sorting on target protein turnover retained as non-core. Reason: Ortholog projection from mouse reflects VPS35-dependent facilitation of protein turnover (such as MDV-mediated lysosomal degradation of DLP1 complexes, PMID:26618722, or cathepsin D-mediated clearance of alpha-synuclein, PMID:24152121); retained as a downstream non-core effect. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. PMID:24152121 While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of Ξ±-synuclein, a causative agent of PD. |
| GO:0031748 D1 dopamine receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Direct binding of VPS35 to the dopamine D1 receptor for endosomal recycling is a validated cargo-recognition interaction. Reason: Wang et al. (PMID:27460146) demonstrated by co-immunoprecipitation that VPS35 interacts with dopamine receptor D1 (DRD1, UniProtKB:P21728) to mediate its endosome-to-plasma-membrane recycling, directly instantiating VPS35's core cargo-recognition function. Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0031748 D1 dopamine receptor binding | IPI PMID:27460146 VPS35 regulates cell surface recycling and signaling of dopa... | ACCEPT | Summary: Direct binding of VPS35 to the dopamine D1 receptor for endosomal recycling is a validated cargo-recognition interaction. Reason: Wang et al. (PMID:27460146) demonstrated by co-immunoprecipitation that VPS35 interacts with dopamine receptor D1 (DRD1, UniProtKB:P21728) to mediate its endosome-to-plasma-membrane recycling, directly instantiating VPS35's core cargo-recognition function. Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0032456 endocytic recycling | IMP PMID:20164305 Retromer-mediated direct sorting is required for proper endo... | ACCEPT | Summary: VPS35 mediates direct endosome-to-plasma-membrane endocytic recycling as part of the SNX27-retromer complex. Reason: Depletion and rescue studies show that VPS35 is required within the SNX27-retromer complex to recycle transmembrane cargoes such as beta2AR, GLUT1, and DMT1-II from endosomes to the plasma membrane. Supporting Evidence: PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:21602791 Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking Ξ²2ARs to the retromer tubule. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0032456 endocytic recycling | IMP PMID:21602791 SNX27 mediates retromer tubule entry and endosome-to-plasma ... | ACCEPT | Summary: VPS35 mediates direct endosome-to-plasma-membrane endocytic recycling as part of the SNX27-retromer complex. Reason: Depletion and rescue studies show that VPS35 is required within the SNX27-retromer complex to recycle transmembrane cargoes such as beta2AR, GLUT1, and DMT1-II from endosomes to the plasma membrane. Supporting Evidence: PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:21602791 Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking Ξ²2ARs to the retromer tubule. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0032456 endocytic recycling | NAS PMID:30072228 Endosomal Retrieval of Cargo: Retromer Is Not Alone. | ACCEPT | Summary: VPS35 mediates direct endosome-to-plasma-membrane endocytic recycling as part of the SNX27-retromer complex. Reason: Depletion and rescue studies show that VPS35 is required within the SNX27-retromer complex to recycle transmembrane cargoes such as beta2AR, GLUT1, and DMT1-II from endosomes to the plasma membrane. Supporting Evidence: PMID:20164305 Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID:21602791 Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking Ξ²2ARs to the retromer tubule. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0032463 negative regulation of protein homooligomerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream role of VPS35 in preventing alpha-synuclein oligomerization and aggregation retained as non-core. Reason: Mouse ortholog projection reflects the role of VPS35 retromer sorting (via CI-MPR/sortilin-dependent cathepsin D delivery) in preventing intracellular oligomerization and aggregation of alpha-synuclein (Follett et al., PMID:24152121; Follett et al., PMID:27385586); retained as an indirect, downstream non-core proteostasis phenotype. Supporting Evidence: PMID:27385586 Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular Ξ±-synuclein-positive aggregates, a hallmark of Parkinson disease. PMID:24152121 While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of Ξ±-synuclein, a causative agent of PD. |
| GO:0036010 protein localization to endosome | IMP PMID:28892079 Retriever is a multiprotein complex for retromer-independent... | KEEP AS NON CORE | Summary: Role of VPS35 in recruiting retromer-associated sorting machinery to endosomal membranes retained as non-core. Reason: VPS35 serves as the endosomal hub that recruits WASH and other retromer-associated sorting factors to endosomal membranes (McNally et al., PMID:28892079; Arighi et al., PMID:15078903); retained as non-core relative to its primary cargo-retrieval process annotations (GO:0042147 and GO:0032456). Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. PMID:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | IBA GO_REF:0000033 | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000120819 Β· VPS35 family node SUPPORTS TRANSFER Endosome-to-Golgi retrieval is conserved across all eukaryotic VPS35 orthologs. SGD:S000003690 Β· yeast VPS35 SUPPORTS TRANSFER Foundational yeast Vps35p experimental evidence. UniProtKB:Q96QK1 Β· human VPS35 SUPPORTS TRANSFER Direct experimental evidence in human. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | IEA GO_REF:0000120 | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | NAS PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | NAS PMID:18193037 Wingless secretion requires endosome-to-Golgi retrieval of W... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042147 retrograde transport, endosome to Golgi | NAS PMID:26220253 Retromer: Structure, function, and roles in mammalian diseas... | ACCEPT | Summary: VPS35 is essential for retromer-mediated retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network. Reason: Depletion or mutation of VPS35 blocks endosome-to-Golgi retrograde retrieval of CI-MPR, sortilin, and Wntless, causing their missorting and lysosomal degradation. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. PMID:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0042176 regulation of protein catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: Broad regulation of protein catabolic process annotation should be refined to specific retromer sorting pathways. Reason: GO:0042176 (regulation of protein catabolic process) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35-positive endosomes to neurites and neuron projections retained as non-core. Reason: In neurons, VPS35-containing endosomes distribute along axons and dendrites to support receptor recycling and spine maintenance (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific anatomical compartment relative to core endosome membrane localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35-positive endosomes to the neuronal soma retained as non-core. Reason: In neurons, VPS35-positive endosomes are abundant in the neuronal cell body as well as neurites (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific anatomical compartment relative to universal endosome membrane localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Pathophysiological role of elevated or mutant VPS35 in excessive mitochondrial fragmentation and neuronal loss retained as non-core. Reason: Wang et al. (PMID:26618722) demonstrated that overexpression of wild-type VPS35 or expression of PD-linked VPS35 mutants (D620N, R524W) causes DLP1-dependent mitochondrial fragmentation and neuronal death in vitro and in vivo; retained as a downstream pathophysiological non-core process. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0045056 transcytosis | IDA PMID:15247922 The mammalian retromer regulates transcytosis of the polymer... | KEEP AS NON CORE | Summary: Specialized role of mammalian retromer in polymeric immunoglobulin receptor (pIgR) transcytosis in polarized epithelial cells retained as non-core. Reason: Verges et al. (PMID:15247922) showed that the mammalian VPS35-VPS29-VPS26 retromer complex promotes basolateral-to-apical transcytosis of pIgR-pIgA in polarized epithelial cells; retained as a cell-type- and cargo-specific manifestation of endosomal sorting. Supporting Evidence: PMID:15247922 Here, we show a function for the mammalian Vps35-Vps29-Vps26 retromer subcomplex in promoting pIgR-pIgA transcytosis. |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to synapses retained as non-core. Reason: In neurons, VPS35 localizes to synaptic compartments where it supports neurotransmitter receptor recycling and dendritic spine maintenance (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific localization relative to universal endosomal membrane localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0045732 positive regulation of protein catabolic process | IGI PMID:25533483 Parkinson's disease genes VPS35 and EIF4G1 interact genetica... | KEEP AS NON CORE | Summary: Downstream role of VPS35 and sortilin in promoting lysosomal clearance of misfolded alpha-synuclein retained as non-core. Reason: Dhungel et al. (PMID:25533483) and Follett et al. (PMID:24152121) showed that VPS35-dependent sorting of sortilin and CI-MPR maintains lysosomal protease delivery required to degrade misfolded proteins including alpha-synuclein; retained as a downstream non-core consequence of hydrolase receptor retrieval. Supporting Evidence: PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. PMID:24152121 While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of Ξ±-synuclein, a causative agent of PD. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Localization of VPS35-positive endosomes to the perinuclear region of the cytoplasm retained as non-core. Reason: Retromer-positive endosomes distribute in the perinuclear cytoplasm and cluster perinuclearly upon expression of the PD-linked VPS35 D620N mutant (Follett et al., PMID:24152121); retained as a broader descriptive cytoplasmic region compared to core endosome membrane localization (GO:0010008). Supporting Evidence: PMID:24152121 We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. |
| GO:0050728 negative regulation of inflammatory response | IGI PMID:25533483 Parkinson's disease genes VPS35 and EIF4G1 interact genetica... | KEEP AS NON CORE | Summary: Downstream genetic effect of VPS35 in limiting neuroinflammatory responses to alpha-synuclein accumulation retained as non-core. Reason: Annotated from genetic interaction with SNCA (P37840) in Dhungel et al. (PMID:25533483); suppression of neuroinflammatory responses is a secondary organismal consequence of retromer-mediated proteostasis, so it is retained as non-core. Supporting Evidence: PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (regulation of developmental process) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute regulation of developmental process; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0050804 modulation of chemical synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in modulating chemical synaptic transmission via receptor recycling retained as non-core. Reason: By recycling neurotransmitter receptors (such as DRD1 and glutamate receptors) to the synaptic membrane and maintaining dendritic spines (Wang et al., PMID:27460146; Wang et al., PMID:26618722), VPS35 modulates chemical synaptic transmission; retained as a downstream cell-type-specific consequence of endosomal recycling. Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
| GO:0050882 voluntary musculoskeletal movement | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (voluntary musculoskeletal movement) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute voluntary musculoskeletal movement; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0051049 regulation of transport | IEA GO_REF:0000117 | MODIFY | Summary: Broad regulation of transport annotation should be refined to specific retromer sorting pathways. Reason: GO:0051049 (regulation of transport) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0051246 regulation of protein metabolic process | IDA PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | MODIFY | Summary: Broad regulation of protein metabolic process annotation should be refined to specific retromer sorting pathways. Reason: GO:0051246 (regulation of protein metabolic process) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0051246 regulation of protein metabolic process | IGI PMID:25533483 Parkinson's disease genes VPS35 and EIF4G1 interact genetica... | MODIFY | Summary: Broad regulation of protein metabolic process annotation should be refined to specific retromer sorting pathways. Reason: GO:0051246 (regulation of protein metabolic process) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0060161 positive regulation of dopamine receptor signaling pathway | IDA PMID:27460146 VPS35 regulates cell surface recycling and signaling of dopa... | KEEP AS NON CORE | Summary: Downstream enhancement of DRD1-mediated cAMP/CREB and ERK signaling via VPS35-dependent DRD1 surface recycling retained as non-core. Reason: Wang et al. (PMID:27460146) demonstrated that VPS35-mediated endosomal recycling of dopamine receptor D1 (DRD1) maintains cell-surface DRD1 levels and thereby supports dopamine-stimulated CREB and ERK phosphorylation; retained as a downstream cargo-specific signaling consequence. Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0061357 positive regulation of Wnt protein secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cargo-specific requirement of VPS35 retromer for Wntless retrieval and Wnt protein secretion retained as non-core. Reason: Retromer is required for Wnt protein secretion because it retrieves the Wnt sorting receptor Wntless (WLS) from endosomes to the TGN, preventing its lysosomal degradation (Belenkaya et al., PMID:18160348; Franch-Marro et al., PMID:18193037); retained as a cargo-specific downstream pathway. Supporting Evidence: PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Proteomic detection of VPS35 in human urinary exosomes retained as non-core. Reason: Gonzales et al. (PMID:19056867) identified VPS35 by LC-MS/MS in human urinary exosomes, which originate as intraluminal vesicles of multivesicular bodies; retained as a non-core proteomic localization resulting from endosomal membrane incorporation into MVB exosomes. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space. Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0090128 regulation of synapse maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in synapse maturation via endosomal receptor sorting retained as non-core. Reason: Ortholog projection from mouse reflects the requirement for VPS35-mediated endosomal receptor recycling and mitochondrial quality control in synaptic development and maturation (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific developmental outcome. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0090141 positive regulation of mitochondrial fission | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Positive regulation of mitochondrial fission via MDV-mediated clearance of inhibitory DLP1 oligomers retained as non-core. Reason: Wang et al. (PMID:26618722) demonstrated that VPS35 promotes mitochondrial fission by binding mitochondrial DLP1 complexes and routing them into mitochondria-derived vesicles for lysosomal turnover; retained as non-core relative to endosomal retromer sorting. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cargo-specific requirement of VPS35 retromer for canonical Wnt signaling via Wntless retrieval retained as non-core. Reason: By retrieving Wntless from endosomes to the TGN to sustain Wnt secretion (Belenkaya et al., PMID:18160348; Franch-Marro et al., PMID:18193037), VPS35 positively regulates canonical Wnt signaling; retained as a downstream cargo-specific signaling effect. Supporting Evidence: PMID:18160348 We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN). PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. |
| GO:0090326 positive regulation of locomotion involved in locomotory behavior | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (positive regulation of locomotion involved in locomotory behavior) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute positive regulation of locomotion involved in locomotory behavior; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0097422 tubular endosome | IDA PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | ACCEPT | Summary: VPS35 localizes to tubular domains of early endosomes where retrograde cargo is concentrated. Reason: Immunoelectron and fluorescence microscopy in PMID:15078903 demonstrate that VPS35 localizes to tubular endosomal domains enriched in CI-MPR prior to transport to the TGN. Supporting Evidence: PMID:15078903 In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. |
| GO:0098691 dopaminergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to dopaminergic synapses retained as non-core. Reason: In dopaminergic neurons, VPS35 localizes to synaptic endosomes and recycles dopamine receptor D1 (Wang et al., PMID:27460146; Wang et al., PMID:26618722); retained as a cell-type-specific synaptic localization relative to core endosome membrane localization. Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
| GO:0098793 presynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to presynaptic terminals retained as non-core. Reason: In neurons, VPS35-positive endosomes localize to presynaptic and postsynaptic compartments to support local membrane protein recycling and bouton maintenance (Wang et al., PMID:26618722; Dhungel et al., PMID:25533483); retained as a cell-type-specific localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. |
| GO:0098794 postsynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to postsynaptic compartments retained as non-core. Reason: In neurons, VPS35-positive endosomes localize to postsynaptic compartments and dendritic spines where retromer recycles neurotransmitter receptors (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0098887 neurotransmitter receptor transport, endosome to postsynaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Specialized neuronal role of VPS35 in recycling neurotransmitter receptors from endosomes to the postsynaptic membrane retained as non-core. Reason: Ortholog projection from mouse reflects the specialized neuronal role of retromer in recycling neurotransmitter receptors (such as dopamine and glutamate receptors) from dendritic endosomes to the postsynaptic membrane (Wang et al., PMID:27460146); retained as a cell-type-specific specialization of core GO:0032456 (endocytic recycling). Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal localization of VPS35 to glutamatergic synapses retained as non-core. Reason: In excitatory cortical and hippocampal neurons, VPS35 localizes to PSD95-positive glutamatergic synapses and dendritic spines (Wang et al., PMID:26618722); retained as a cell-type-specific anatomical localization relative to core endosome membrane localization. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
| GO:0099073 mitochondrion-derived vesicle | IDA PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Localization of VPS35 to mitochondria-derived vesicles (MDVs) retained as non-core. Reason: Wang et al. (PMID:26618722) showed by in vitro reconstitution, immuno-EM, and confocal imaging that VPS35 localizes to and promotes the formation of TOM20/DLP1-positive mitochondria-derived vesicles; retained as a specialized non-core compartment alongside its canonical endosomal retromer localization. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0099074 mitochondrion to lysosome vesicle-mediated transport | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Role of VPS35 in mitochondria-derived vesicle transport of DLP1 complexes to lysosomes retained as non-core. Reason: Wang et al. (PMID:26618722) demonstrated that VPS35 mediates the transport of DLP1-containing mitochondria-derived vesicles to lysosomes for degradation; retained as a specialized non-core trafficking route alongside canonical endosomal retromer sorting. Supporting Evidence: PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:0099175 regulation of postsynapse organization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in regulating postsynapse organization retained as non-core. Reason: In neurons, VPS35-mediated endosomal sorting and mitochondrial dynamics maintain postsynaptic organization and PSD95-positive dendritic spines (Wang et al., PMID:26618722; Wang et al., PMID:27460146); retained as a cell-type-specific downstream neuronal phenotype. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0099638 obsolete endosome to plasma membrane protein transport | IBA GO_REF:0000033 | MODIFY | Summary: Obsolete endosome to plasma membrane protein transport term replaced by endocytic recycling. Reason: GO:0099638 is obsolete; VPS35's direct role in SNX27-retromer-mediated endosome-to-plasma-membrane recycling is captured by GO:0032456 (endocytic recycling). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000120819 Β· VPS35 family node SUPPORTS TRANSFER Conserved retromer VPS35 node; term itself was obsoleted in GO. UniProtKB:Q96QK1 Β· human VPS35 SUPPORTS TRANSFER Direct experimental evidence in human. Proposed replacements: endocytic recycling Supporting Evidence: PMID:21602791 Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking Ξ²2ARs to the retromer tubule. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:0099639 neurotransmitter receptor transport, endosome to plasma membrane | IDA PMID:27460146 VPS35 regulates cell surface recycling and signaling of dopa... | KEEP AS NON CORE | Summary: Cargo-specific endosome-to-plasma-membrane recycling of neurotransmitter receptors (such as DRD1) retained as non-core. Reason: Wang et al. (PMID:27460146) demonstrated that VPS35 binds DRD1 and promotes its endosome-to-cell-surface recycling; retained as a cargo- and neuron-specific specialization of core GO:0032456 (endocytic recycling). Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0099639 neurotransmitter receptor transport, endosome to plasma membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cargo-specific endosome-to-plasma-membrane recycling of neurotransmitter receptors (such as DRD1) retained as non-core. Reason: Wang et al. (PMID:27460146) demonstrated that VPS35 binds DRD1 and promotes its endosome-to-cell-surface recycling; retained as a cargo- and neuron-specific specialization of core GO:0032456 (endocytic recycling). Supporting Evidence: PMID:27460146 These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. |
| GO:0140312 cargo adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: VPS35 contributes to cargo adaptor activity as the central scaffold of the retromer cargo-selective complex. Reason: VPS35 is the central alpha-helical solenoid subunit of the retromer cargo-selective complex; its N-terminal region binds VPS26A/B and cooperates with SNX3 to couple recognition of canonical omega-Phi-[L/M] sorting motifs in transmembrane cargoes to endosomal membrane recruitment (Lucas et al., PMID:27889239), while its C-terminal solenoid wraps around VPS29 (Hierro et al., PMID:17891154) and forms the legs of membrane-assembled retromer arches (Kovtun et al., PMID:30224749). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000120819 Β· VPS35 family node SUPPORTS TRANSFER Conserved across all eukaryotic VPS35 orthologs. SGD:S000003690 Β· yeast VPS35 SUPPORTS TRANSFER Foundational yeast Vps35p cargo-recognition evidence. Supporting Evidence: PMID:27889239 Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. PMID:17891154 Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. PMID:30224749 This reveals a membrane-associated Vps5 array, from which arches of retromer extend away from the membrane surface. Vps35 forms the 'legs' of these arches, and Vps29 resides at the apex where it is free to interact with regulatory factors. PMID:27385586 Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. |
| GO:0150052 regulation of postsynapse assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in regulating postsynapse assembly retained as non-core. Reason: Ortholog projection from mouse reflects the requirement for VPS35-mediated endosomal receptor trafficking and mitochondrial quality control in assembling and maintaining PSD95-positive postsynaptic structures (Wang et al., PMID:26618722); retained as a cell-type-specific downstream neuronal process. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
| GO:1902823 negative regulation of late endosome to lysosome transport | IMP PMID:23563491 A global analysis of SNX27-retromer assembly and cargo speci... | KEEP AS NON CORE | Summary: Prevention of default late endosome-to-lysosome degradation of recycling cargoes by SNX27-retromer retained as non-core. Reason: Steinberg et al. (PMID:23563491) showed that SNX27-retromer rescues transmembrane cargoes from entry into the late endosome-to-lysosome degradative pathway by diverting them into recycling tubules; because preventing lysosomal delivery is the protective consequence of active endosomal retrieval, this regulatory term is retained as non-core. Supporting Evidence: PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1902950 regulation of dendritic spine maintenance | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in maintaining dendritic spines retained as non-core. Reason: Wang et al. (PMID:26618722) demonstrated that perturbation of VPS35 in primary cortical neurons causes loss of dendritic spines that is rescued by inhibiting excessive mitochondrial fission; retained as a cell-type-specific downstream neuronal phenotype. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
| GO:1903181 positive regulation of dopamine biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Downstream pleiotropic or transcriptional readout (positive regulation of dopamine biosynthetic process) represents over-annotation. Reason: VPS35 is an endosomal cargo-sorting scaffold and does not directly execute positive regulation of dopamine biosynthetic process; changes in gene expression, development, or locomotion upon VPS35 perturbation are indirect downstream consequences of altered receptor and transporter trafficking. Supporting Evidence: PMID:24115276 VPS35 is well described as a key component of the retromer complex, important for the sorting and retrograde transport of membrane-localized proteins from endosomes to the trans-Golgi network PMID:26618722 VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. |
| GO:1903828 negative regulation of protein localization | IEA GO_REF:0000107 | MODIFY | Summary: Broad negative regulation of protein localization annotation should be refined to specific retromer sorting pathways. Reason: GO:1903828 (negative regulation of protein localization) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1903829 positive regulation of protein localization | IEA GO_REF:0000117 | MODIFY | Summary: Broad positive regulation of protein localization annotation should be refined to specific retromer sorting pathways. Reason: GO:1903829 (positive regulation of protein localization) describes a generic or downstream consequence of retromer-mediated sorting; VPS35's direct biological processes are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Proposed replacements: retrograde transport, endosome to Golgi endocytic recycling Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:18193037 Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1904377 positive regulation of protein localization to cell periphery | IMP PMID:25533483 Parkinson's disease genes VPS35 and EIF4G1 interact genetica... | KEEP AS NON CORE | Summary: Downstream role of VPS35-mediated endosomal recycling in promoting cell-surface protein localization retained as non-core. Reason: By driving endosome-to-plasma-membrane recycling of transmembrane cargoes in conserved models (Dhungel et al., PMID:25533483; Steinberg et al., PMID:23563491), VPS35 increases cargo localization to the cell periphery; retained as non-core because GO:0032456 (endocytic recycling) directly captures the transport mechanism. Supporting Evidence: PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1904377 positive regulation of protein localization to cell periphery | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Downstream role of VPS35-mediated endosomal recycling in promoting cell-surface protein localization retained as non-core. Reason: By driving endosome-to-plasma-membrane recycling of transmembrane cargoes in conserved models (Dhungel et al., PMID:25533483; Steinberg et al., PMID:23563491), VPS35 increases cargo localization to the cell periphery; retained as non-core because GO:0032456 (endocytic recycling) directly captures the transport mechanism. Supporting Evidence: PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1905166 negative regulation of lysosomal protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Prevention of lysosomal degradation of retrieved transmembrane receptors by VPS35 retained as non-core. Reason: By retrieving transmembrane receptors (such as CI-MPR, DMT1-II, and SNX27 cargoes) from endosomes, retromer prevents their lysosomal proteolysis (Arighi et al., PMID:15078903; Steinberg et al., PMID:23563491); retained as non-core because it describes the protective consequence of core endosomal retrieval. Supporting Evidence: PMID:15078903 Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. PMID:23563491 Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. |
| GO:1905606 regulation of presynapse assembly | ISS PMID:25533483 Parkinson's disease genes VPS35 and EIF4G1 interact genetica... | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in regulating presynapse assembly retained as non-core. Reason: Ortholog projection from C. elegans (Dhungel et al., PMID:25533483) reflects a role for VPS35-dependent endosomal sorting in presynaptic organization; retained as a cell-type-specific downstream developmental outcome. Supporting Evidence: PMID:25533483 Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. |
| GO:2000331 regulation of terminal button organization | IMP PMID:26618722 Parkinson's disease-associated mutant VPS35 causes mitochond... | KEEP AS NON CORE | Summary: Downstream neuronal role of VPS35 in maintaining synaptic bouton organization retained as non-core. Reason: Wang et al. (PMID:26618722) showed that VPS35 perturbation in primary cortical neurons causes loss of PSD95-positive synaptic boutons that is rescued by inhibiting excessive mitochondrial fission; retained as a cell-type-specific downstream neuronal phenotype. Supporting Evidence: PMID:26618722 Loss of dendritic spines and PSD95-positive boutons was apparent in primary neurons expressing WT or mutant VPS35 (Fig. 3e-g). |
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Experiment: Determine cryo-ET structures of native membrane-assembled retromer arches in wild-type and VPS35-D620N knock-in human iPSC-derived dopaminergic neurons and quantify FAM21/WASH recruitment dynamics.
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