Vacuolar protein sorting-associated protein 26A (VPS26A) is the arrestin-fold subunit of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29) on early and tubular endosomal membranes. Its C-terminal lobe binds the N-terminal alpha-helical solenoid of VPS35, while its interface with VPS35 and SNX3 directly recognizes canonical omega-Phi-[L/M] sorting motifs in retrograde cargoes such as CI-MPR (IGF2R), sortilin, Wntless, and DMT1-II for endosome-to-Golgi retrieval, and its beta-sandwich surface binds the PDZ domain of SNX27 to drive endosome-to-plasma membrane recycling of transmembrane receptors.
| 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role 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; VPS26A's assembly into the retromer cargo-selective complex and its cooperative cargo-adaptor role are captured by GO:0030906 and GO:0140312. |
| GO:0005737 cytoplasm | EXP PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | MODIFY | Summary: Cytoplasm localization is true but too broad; refine to cytosol and endosome membrane. Reason: VPS26A cycles between a soluble cytosolic pool and the cytoplasmic face of endosomal membranes as part of the retromer complex; GO:0005737 (cytoplasm) is refined to GO:0005829 (cytosol) and GO:0010008 (endosome membrane). Proposed replacements: cytosol endosome membrane 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Cytoplasm localization is true but too broad; refine to cytosol and endosome membrane. Reason: VPS26A cycles between a soluble cytosolic pool and the cytoplasmic face of endosomal membranes as part of the retromer complex; GO:0005737 (cytoplasm) is refined to GO:0005829 (cytosol) and GO:0010008 (endosome membrane). Proposed replacements: cytosol endosome membrane 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0005764 lysosome | IDA GO_REF:0000052 | MODIFY | Summary: High-throughput immunofluorescence endolysosomal puncta reflect endosomal localization; refine laterally to endosome. Reason: High-throughput immunofluorescence detects endolysosomal puncta, but cell-biological and structural studies demonstrate that VPS26A localizes to early and maturing endosomes prior to lysosomal fusion; GO:0005764 (lysosome) is laterally corrected to GO:0005768 (endosome), which VPS26A already carries. Proposed replacements: endosome 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0005768 endosome | IBA GO_REF:0000033 | ACCEPT | Summary: VPS26A localizes to and functions at endosomes as a subunit of the retromer complex. Reason: Direct immunofluorescence, structural, and functional studies establish that VPS26A associates with endosomes to mediate retromer-dependent cargo sorting. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000260563 · PTHR12233 ancestral node SUPPORTS TRANSFER Endosomal localization is conserved across the VPS26/DSCR3 family. UniProtKB:O75436 · human VPS26A SUPPORTS TRANSFER Direct experimental support in human. 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:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005768 endosome | IDA GO_REF:0000052 | ACCEPT | Summary: VPS26A localizes to and functions at endosomes as a subunit of the retromer complex. Reason: Direct immunofluorescence, structural, and functional studies establish that VPS26A associates with endosomes to mediate retromer-dependent 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:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005768 endosome | IDA PMID:20682791 A protein interaction network for Ecm29 links the 26 S prote... | ACCEPT | Summary: VPS26A localizes to and functions at endosomes as a subunit of the retromer complex. Reason: Direct immunofluorescence, structural, and functional studies establish that VPS26A associates with endosomes to mediate retromer-dependent 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:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005768 endosome | IEA GO_REF:0000107 | ACCEPT | Summary: VPS26A localizes to and functions at endosomes as a subunit of the retromer complex. Reason: Direct immunofluorescence, structural, and functional studies establish that VPS26A associates with endosomes to mediate retromer-dependent 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:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005769 early endosome | EXP PMID:16190980 A novel mammalian retromer component, Vps26B. | ACCEPT | Summary: VPS26A localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Multiple independent studies demonstrate that VPS26A localizes to early endosomes, particularly their tubular sorting domains, to retrieve CI-MPR and other receptors. 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:16190980 The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. PMID:16732284 The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005769 early endosome | EXP PMID:16732284 The retromer subunit Vps26 has an arrestin fold and binds Vp... | ACCEPT | Summary: VPS26A localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Multiple independent studies demonstrate that VPS26A localizes to early endosomes, particularly their tubular sorting domains, to retrieve CI-MPR and other receptors. 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:16190980 The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. PMID:16732284 The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005769 early endosome | EXP PMID:20682791 A protein interaction network for Ecm29 links the 26 S prote... | ACCEPT | Summary: VPS26A localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Multiple independent studies demonstrate that VPS26A localizes to early endosomes, particularly their tubular sorting domains, to retrieve CI-MPR and other receptors. 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:16190980 The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. PMID:16732284 The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005769 early endosome | IDA PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | ACCEPT | Summary: VPS26A localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Multiple independent studies demonstrate that VPS26A localizes to early endosomes, particularly their tubular sorting domains, to retrieve CI-MPR and other receptors. 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:16190980 The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. PMID:16732284 The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005769 early endosome | IEA GO_REF:0000120 | ACCEPT | Summary: VPS26A localizes to early endosomes where retromer sorts transmembrane cargoes. Reason: Multiple independent studies demonstrate that VPS26A localizes to early endosomes, particularly their tubular sorting domains, to retrieve CI-MPR and other receptors. 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:16190980 The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. PMID:16732284 The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247836 | ACCEPT | Summary: VPS26A exists in a soluble cytosolic pool that is recruited onto endosomal membranes. Reason: Fractionation and biochemical studies show that the VPS35-VPS26-VPS29 heterotrimer partitions between a soluble cytosolic pool 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247839 | ACCEPT | Summary: VPS26A exists in a soluble cytosolic pool that is recruited onto endosomal membranes. Reason: Fractionation and biochemical studies show that the VPS35-VPS26-VPS29 heterotrimer partitions between a soluble cytosolic pool 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3247849 | ACCEPT | Summary: VPS26A exists in a soluble cytosolic pool that is recruited onto endosomal membranes. Reason: Fractionation and biochemical studies show that the VPS35-VPS26-VPS29 heterotrimer partitions between a soluble cytosolic pool 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. file:human/VPS26A/VPS26A-uniprot.txt Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. |
| GO:0006886 intracellular protein transport | IBA GO_REF:0000033 | MODIFY | Summary: Broad intracellular protein transport term should be refined to specific retromer pathways. Reason: GO:0006886 (intracellular protein transport) is true but overly general for VPS26A; its specific transport roles are retrograde transport from endosome to Golgi (GO:0042147) and endocytic recycling to the plasma membrane (GO:0032456). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000260563 · PTHR12233 ancestral node SUPPORTS TRANSFER Family root averages retromer (endosome-to-Golgi and recycling) and retriever (endocytic recycling) into generic intracellular protein transport. FB:FBgn0014411 · Drosophila Vps26 SUPPORTS TRANSFER Drosophila Vps26 mediates endosome-to-Golgi retrieval and endocytic recycling. 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: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 β2ARs to the retromer tubule. |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | MODIFY | Summary: Broad intracellular protein transport term should be refined to specific retromer pathways. Reason: GO:0006886 (intracellular protein transport) is true but overly general for VPS26A; its specific transport roles 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: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 β2ARs to the retromer tubule. |
| GO:0010008 endosome membrane | IDA PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | ACCEPT | Summary: VPS26A is recruited to the cytoplasmic surface of the endosome membrane. Reason: Structural and cell biological studies show that VPS26A directly contacts SNX3 and membrane-proximal cargo tails on the cytoplasmic leaflet of the endosome membrane (PMID:27889239, PMID:27385586, PMID:22431521). 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: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:22431521 We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0010008 endosome membrane | IDA PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS26A is recruited to the cytoplasmic surface of the endosome membrane. Reason: Structural and cell biological studies show that VPS26A directly contacts SNX3 and membrane-proximal cargo tails on the cytoplasmic leaflet of the endosome membrane (PMID:27889239, PMID:27385586, PMID:22431521). 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: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:22431521 We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: VPS26A is recruited to the cytoplasmic surface of the endosome membrane. Reason: Structural and cell biological studies show that VPS26A directly contacts SNX3 and membrane-proximal cargo tails on the cytoplasmic leaflet of the endosome membrane (PMID:27889239, PMID:27385586, PMID:22431521). 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: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:22431521 We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0010008 endosome membrane | NAS PMID:30072228 Endosomal Retrieval of Cargo: Retromer Is Not Alone. | ACCEPT | Summary: VPS26A is recruited to the cytoplasmic surface of the endosome membrane. Reason: Structural and cell biological studies show that VPS26A directly contacts SNX3 and membrane-proximal cargo tails on the cytoplasmic leaflet of the endosome membrane (PMID:27889239, PMID:27385586, PMID:22431521). 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: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:22431521 We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0016241 regulation of macroautophagy | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Indirect downstream effect of retromer loss on lysosomal hydrolase delivery and autophagic cargo degradation. Reason: In Vps26- and Vps35-deficient cells, autophagosome formation and autophagy initiation are intact (consistent with the curated NOT|involved_in GO:0010506 annotation on retromer subunit VPS29), whereas late-stage autophagic cargo degradation is impaired indirectly due to defective CI-MPR-mediated lysosomal hydrolase maintenance (PMID:26172538). 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:0016241 regulation of macroautophagy | TAS PMID:26172538 Retromer Ensures the Degradation of Autophagic Cargo by Main... | KEEP AS NON CORE | Summary: Indirect downstream effect of retromer loss on lysosomal hydrolase delivery and autophagic cargo degradation. Reason: In Vps26- and Vps35-deficient cells, autophagosome formation and autophagy initiation are intact (consistent with the curated NOT|involved_in GO:0010506 annotation on retromer subunit VPS29), whereas late-stage autophagic cargo degradation is impaired indirectly due to defective CI-MPR-mediated lysosomal hydrolase maintenance (PMID:26172538). 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 | IDA PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS26A is an integral subunit of the retromer complex. Reason: Biochemical purification, co-immunoprecipitation, and crystal structures confirm that VPS26A is one of the two paralogous arrestin-fold subunits of the mammalian 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:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. 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:0030904 retromer complex | IDA PMID:28892079 Retriever is a multiprotein complex for retromer-independent... | ACCEPT | Summary: VPS26A is an integral subunit of the retromer complex. Reason: Biochemical purification, co-immunoprecipitation, and crystal structures confirm that VPS26A is one of the two paralogous arrestin-fold subunits of the mammalian 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:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. 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:0030904 retromer complex | IEA GO_REF:0000107 | ACCEPT | Summary: VPS26A is an integral subunit of the retromer complex. Reason: Biochemical purification, co-immunoprecipitation, and crystal structures confirm that VPS26A is one of the two paralogous arrestin-fold subunits of the mammalian 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:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. 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:0030904 retromer complex | NAS PMID:18193037 Wingless secretion requires endosome-to-Golgi retrieval of W... | ACCEPT | Summary: VPS26A is an integral subunit of the retromer complex. Reason: Biochemical purification, co-immunoprecipitation, and crystal structures confirm that VPS26A is one of the two paralogous arrestin-fold subunits of the mammalian 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:28892079 We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. 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:0030906 retromer, cargo-selective complex | IBA GO_REF:0000033 | ACCEPT | Summary: VPS26A is a core subunit of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS26A binds the N-terminal region of VPS35 to assemble the heterotrimeric retromer cargo-selective complex and forms the binding pocket for canonical omega-Phi-[L/M] cargo motifs. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000260564 · VPS26 clade node SUPPORTS TRANSFER Subfamily-specific node for canonical retromer Vps26 orthologs. SGD:S000003589 · yeast PEP8/VPS26 SUPPORTS TRANSFER Canonical yeast retromer Vps26 subunit. UniProtKB:O75436 · human VPS26A 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: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:0030906 retromer, cargo-selective complex | IDA PMID:27385586 Parkinson Disease-linked Vps35 R524W Mutation Impairs the En... | ACCEPT | Summary: VPS26A is a core subunit of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS26A binds the N-terminal region of VPS35 to assemble the heterotrimeric retromer cargo-selective complex and forms the binding pocket for canonical omega-Phi-[L/M] cargo motifs. 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: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:0030906 retromer, cargo-selective complex | IPI PMID:11102511 Human orthologs of yeast vacuolar protein sorting proteins V... | ACCEPT | Summary: VPS26A is a core subunit of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS26A binds the N-terminal region of VPS35 to assemble the heterotrimeric retromer cargo-selective complex and forms the binding pocket for canonical omega-Phi-[L/M] cargo motifs. 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: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:0030906 retromer, cargo-selective complex | NAS PMID:26220253 Retromer: Structure, function, and roles in mammalian diseas... | ACCEPT | Summary: VPS26A is a core subunit of the heterotrimeric retromer cargo-selective complex (VPS35-VPS26-VPS29). Reason: VPS26A binds the N-terminal region of VPS35 to assemble the heterotrimeric retromer cargo-selective complex and forms the binding pocket for canonical omega-Phi-[L/M] cargo motifs. 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: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:0031982 vesicle | IDA PMID:20682791 A protein interaction network for Ecm29 links the 26 S prote... | MODIFY | Summary: Generic vesicle localization should be refined to early endosome and tubular endosome. Reason: GO:0031982 (vesicle) is overly general; PMID:20682791 and PMID:15078903 demonstrate that VPS26A localizes specifically to early endosomes (GO:0005769) and tubular endosomal sorting domains (GO:0097422). Proposed replacements: early endosome tubular endosome Supporting Evidence: PMID:20682791 Another membrane-associated component identified in similar analyses was Vps26A, which IF images show is present on a subset of Ecm29-positive vesicles 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:0032456 endocytic recycling | IMP PMID:21602791 SNX27 mediates retromer tubule entry and endosome-to-plasma ... | ACCEPT | Summary: VPS26A directly binds the PDZ domain of SNX27 to mediate endocytic recycling of transmembrane cargoes to the plasma membrane. Reason: VPS26A interacts directly with a conserved beta-hairpin in the SNX27 PDZ domain to couple retromer to direct endosome-to-plasma-membrane recycling of PDZ-binding receptors such as beta2AR and GLUT1 (PMID:23563491, PMID:25136126, PMID:21602791). 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. PMID:25136126 Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. 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 β2ARs to the retromer tubule. 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: VPS26A directly binds the PDZ domain of SNX27 to mediate endocytic recycling of transmembrane cargoes to the plasma membrane. Reason: VPS26A interacts directly with a conserved beta-hairpin in the SNX27 PDZ domain to couple retromer to direct endosome-to-plasma-membrane recycling of PDZ-binding receptors such as beta2AR and GLUT1 (PMID:23563491, PMID:25136126, PMID:21602791). 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. PMID:25136126 Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. 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 β2ARs to the retromer tubule. PMID:30072228 Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. |
| GO:0042147 retrograde transport, endosome to Golgi | IBA GO_REF:0000033 | ACCEPT | Summary: VPS26A is essential for retromer-mediated retrograde transport from endosomes to the trans-Golgi network. Reason: RNAi depletion and structural studies show that VPS26A is required within the retromer CSC to recognize and retrieve acid hydrolase receptors (CI-MPR, sortilin) and Wntless from endosomes to the TGN. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000260564 · VPS26 clade node SUPPORTS TRANSFER Conserved retromer Vps26 clade. SGD:S000003589 · yeast PEP8/VPS26 SUPPORTS TRANSFER Foundational yeast retromer subunit. UniProtKB:O75436 · human VPS26A 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: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: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: VPS26A is essential for retromer-mediated retrograde transport from endosomes to the trans-Golgi network. Reason: RNAi depletion and structural studies show that VPS26A is required within the retromer CSC to recognize and retrieve acid hydrolase receptors (CI-MPR, sortilin) and Wntless from endosomes to the TGN. 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: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: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: VPS26A is essential for retromer-mediated retrograde transport from endosomes to the trans-Golgi network. Reason: RNAi depletion and structural studies show that VPS26A is required within the retromer CSC to recognize and retrieve acid hydrolase receptors (CI-MPR, sortilin) and Wntless from endosomes to the TGN. 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: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: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: VPS26A is essential for retromer-mediated retrograde transport from endosomes to the trans-Golgi network. Reason: RNAi depletion and structural studies show that VPS26A is required within the retromer CSC to recognize and retrieve acid hydrolase receptors (CI-MPR, sortilin) and Wntless from endosomes to the TGN. 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: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:26220253 Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. |
| GO:0097422 tubular endosome | IDA PMID:15078903 Role of the mammalian retromer in sorting of the cation-inde... | ACCEPT | Summary: VPS26A localizes to tubular domains of early endosomes where retrograde cargo is concentrated. Reason: Immunoelectron and fluorescence microscopy in PMID:15078903 demonstrate that VPS26A localizes to tubular endosomal domains enriched in CI-MPR prior to TGN export. 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:0140312 cargo adaptor activity | IDA PMID:27889239 Structural Mechanism for Cargo Recognition by the Retromer C... | NEW | Summary: VPS26A directly forms the omega-Phi-[L/M] cargo-binding pocket with SNX3 and binds the SNX27 PDZ domain to mediate retromer cargo adaptor activity. Reason: X-ray crystallography of the SNX3-retromer-DMT1-II complex (PMID:27889239) demonstrates that VPS26A and SNX3 directly form the binding site for canonical hydrophobic omega-Phi-[L/M] recycling signals, and structural/proteomic analyses of SNX27-retromer (PMID:23563491, PMID:25136126) show that the arrestin-like fold of VPS26A binds an exposed beta-hairpin of the SNX27 PDZ domain to allosterically enhance PDZ-cargo affinity; retromer subunits VPS35 and VPS29 already carry GO:0140312 (cargo adaptor activity) in GOA. 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: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:25136126 Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. |
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Experiment: Compare quantitative endosomal cargo proteomes in isogenic human cells expressing only VPS26A or VPS26B using proximity biotinylation and cryo-ET on tubular endosomes.
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