id: Q9P2R3 gene_symbol: ANKFY1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'ANKFY1 encodes Rabankyrin-5, a large ankyrin-repeat, BTB/POZ, and FYVE-domain protein that acts on PI3P- and Rab5-positive endosomal membranes. It binds activated Rab5-family GTPases and phosphatidylinositol phosphate lipids to regulate early endosome fusion, macropinocytosis, retromer-dependent endosome-to-Golgi and Golgi-to-lysosome trafficking, and receptor internalization. Recent work shows that ANKFY1 also recruits and stabilizes ATG2A on PI3P-rich endosomal membranes during autophagy, promoting ATG2A-mediated lipid transfer from endosomes to phagophores for autophagosome growth and completion.' alternative_products: - name: '1' id: Q9P2R3-1 - name: '2' id: Q9P2R3-2 sequence_note: VSP_035607 - name: '4' id: Q9P2R3-4 sequence_note: VSP_041447 existing_annotations: - term: id: GO:0010008 label: endosome membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Endosome membrane localization/activity is well supported for ANKFY1/Rabankyrin-5. action: ACCEPT reason: ANKFY1 is a FYVE-domain Rab5 effector that binds PI3P and localizes on early/endosomal membranes; this location is central to its endosomal trafficking and ATG2A-bridging roles. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - &id003 reference_id: PMID:15328530 supporting_text: novel PI(3)P-binding Rab5 effector, Rabankyrin-5, which localises to early endosomes and stimulates their fusion activity - &id009 reference_id: PMID:15328530 supporting_text: Rabankyrin-5 binds most strongly to PI(3)P - &id007 reference_id: PMID:38622126 supporting_text: ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores - term: id: GO:0031267 label: small GTPase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Small GTPase binding is directly supported by Rab5 and RhoD/RAB-family interaction evidence. action: ACCEPT reason: Rabankyrin-5 was identified as a GTP-dependent Rab5 effector, and additional disease/trafficking work supports interaction with RAB5-regulatory machinery; this is a core molecular function. additional_reference_ids: - PMID:15328530 - PMID:24102721 - PMID:29959197 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - &id010 reference_id: PMID:15328530 supporting_text: Rabankyrin-5 binds to Rab5 specifically, directly, and GTP dependently - &id013 reference_id: PMID:24102721 supporting_text: RhoD binds to the Rab5 effector Rabankyrin-5 - &id006 reference_id: PMID:29959197 supporting_text: GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5 - term: id: GO:0042147 label: retrograde transport, endosome to Golgi evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Endosome-to-Golgi retrograde transport is supported by Rank-5/retromer evidence. action: ACCEPT reason: Rank-5 interacts and colocalizes with retromer cargo-recognition components, and Rank-5 depletion impairs mannose 6-phosphate receptor retrieval from endosomes to the Golgi. additional_reference_ids: &id001 - PMID:22284051 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - &id005 reference_id: PMID:22284051 supporting_text: Rank-5 colocalizes and interacts with components of the retromer complex such as vacuolar protein sorting 26 (Vps26) - &id002 reference_id: PMID:22284051 supporting_text: depletion of Rank-5 causes mislocalization of Vps26 and affects both the retrieval of mannose 6-phosphate receptor transport to the Golgi from endosomes and biosynthetic transport - term: id: GO:0090160 label: Golgi to lysosome transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Golgi-to-lysosome/biosynthetic transport is supported as part of the Rank-5 retromer-trafficking phenotype. action: ACCEPT reason: The same Rank-5 depletion experiments that disrupt retromer distribution also affect biosynthetic transport, consistent with a role in endosome/Golgi/lysosome trafficking. additional_reference_ids: *id001 supported_by: - *id002 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cytoplasmic localization is supported but is less informative than endosome-membrane localization. action: KEEP_AS_NON_CORE reason: ANKFY1 was initially described as a cytoplasmic protein and is present in soluble fractions, but the biologically informative location is its recruitment to PI3P/Rab5-positive endosomal membranes. additional_reference_ids: - PMID:10940552 - PMID:15328530 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - &id004 reference_id: PMID:10940552 supporting_text: Ankhzn protein is ubiquitously expressed in a spatiotemporal-specific manner and is located on endosomes - &id008 reference_id: PMID:10940552 supporting_text: present in both membrane and soluble fractions obtained on subcellular fractionation - *id003 - term: id: GO:0005768 label: endosome evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Endosome localization is supported and relevant to ANKFY1 function. action: ACCEPT reason: The original ANKHZN paper and later Rabankyrin-5 studies place the protein on endosomes, where it binds Rab5/PI3P and coordinates endocytic trafficking. additional_reference_ids: &id012 - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id004 - *id003 - term: id: GO:0005769 label: early endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Early endosome localization is supported by Rabankyrin-5 colocalization with Rab5/EEA1-positive compartments and later functional studies. action: ACCEPT reason: ANKFY1/Rabankyrin-5 localizes to early endosomes and its endosomal localization is required for endosomal fusion, retromer-related trafficking, and ATG2A recruitment during autophagy stimulation. additional_reference_ids: - PMID:15328530 - PMID:22284051 - PMID:29959197 - PMID:38622126 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id003 - *id005 - *id006 - *id007 - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytosol localization is supported as a source pool but is not the main functional location. action: KEEP_AS_NON_CORE reason: ANKFY1 occurs in soluble and membrane-associated fractions; the reviewed functional evidence points to membrane recruitment at PI3P/Rab5-positive endosomes. additional_reference_ids: - PMID:10940552 - PMID:15328530 supported_by: - *id008 - *id003 - term: id: GO:0010008 label: endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Endosome membrane localization/activity is well supported for ANKFY1/Rabankyrin-5. action: ACCEPT reason: ANKFY1 is a FYVE-domain Rab5 effector that binds PI3P and localizes on early/endosomal membranes; this location is central to its endosomal trafficking and ATG2A-bridging roles. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id003 - *id009 - *id007 - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Generic membrane localization is supported but too broad to represent the core location. action: KEEP_AS_NON_CORE reason: Membrane association is real, but the more informative annotation is endosome membrane/early endosome, where ANKFY1 binds PI3P and functions with Rab5 and ATG2A. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id008 - *id003 - *id007 - term: id: GO:0046872 label: metal ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Metal ion binding is a broad domain-derived proxy for the FYVE zinc finger and should be replaced by the directly demonstrated lipid-binding activity. action: MODIFY reason: The FYVE domain is biologically important because it binds PI3P-containing membranes; direct lipid-binding experiments support phosphatidylinositol phosphate binding, while generic metal ion binding is not informative for ANKFY1 function. proposed_replacement_terms: - id: GO:1901981 label: phosphatidylinositol phosphate binding additional_reference_ids: - PMID:15328530 - PMID:38622126 supported_by: - *id009 - &id015 reference_id: PMID:38622126 supporting_text: enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15328530 qualifier: enables supporting_entities: - UniProtKB:P20339 review: summary: The generic protein-binding row reflects Rab5 interaction and should be replaced by small GTPase binding. action: MODIFY reason: The publication demonstrates specific, direct, GTP-dependent Rab5 binding; GO:0031267 captures the molecular function better than generic protein binding. proposed_replacement_terms: - id: GO:0031267 label: small GTPase binding additional_reference_ids: - PMID:15328530 supported_by: - *id010 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables supporting_entities: - UniProtKB:P60520 review: summary: The generic protein-binding row reflects ATG8/GABARAP-family association in a high-throughput autophagy network. action: MODIFY reason: The evidence is a proteomic autophagy-network interaction, so the more specific molecular-function replacement is ubiquitin-like protein binding; it should be treated as non-core relative to Rab5/PI3P/endosomal trafficking. proposed_replacement_terms: - id: GO:0032182 label: ubiquitin-like protein binding additional_reference_ids: - PMID:20562859 supported_by: - reference_id: PMID:20562859 supporting_text: The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins - reference_id: PMID:20562859 supporting_text: FYVE domain-containing proteins FYCO1 and ANKFY1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22284051 qualifier: enables supporting_entities: - UniProtKB:Q9H4M9 review: summary: The generic protein-binding row reflects Rank-5 binding to the EHD1 EH domain. action: MODIFY reason: Rank-5 contains an NPFED motif that binds the EHD1 EH domain; GO:1990175 EH domain binding captures this interaction better than generic protein binding. proposed_replacement_terms: - id: GO:1990175 label: EH domain binding additional_reference_ids: - PMID:22284051 supported_by: - &id011 reference_id: PMID:22284051 supporting_text: binding occurs between the EH domain of EHD1 and the NPFED motif of Rank-5 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27189942 qualifier: enables supporting_entities: - UniProtKB:Q9H4M9 review: summary: The local cached article does not provide ANKFY1-specific text for this generic EHD1/Q9H4M9 interaction row. action: UNDECIDED reason: The abstract supports EHD paralog binding to NPF-containing partners generally, but the cached text available locally does not document the ANKFY1/Rabankyrin-5 interaction with EHD1 specifically. A replacement such as EH domain binding may be appropriate if full interaction evidence is checked, but this row should remain undecided until the specific evidence is accessible. additional_reference_ids: - PMID:27189942 - PMID:22284051 supported_by: - reference_id: PMID:27189942 supporting_text: EHD proteins have an EH domain that interacts with proteins containing an NPF motif - *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27189942 qualifier: enables supporting_entities: - UniProtKB:Q9NZN3 review: summary: The local cached article does not provide ANKFY1-specific text for this generic EHD3/Q9NZN3 interaction row. action: UNDECIDED reason: The GOA includes a distinct PMID:27189942 IPI row for EHD3/Q9NZN3. The cached abstract supports EHD-family EH-domain recognition of NPF-containing partners and distinguishes EHD1 from EHD3, but it does not expose ANKFY1/Rabankyrin-5-specific interaction evidence for this partner. This row should remain undecided until the specific IntAct/full-text evidence is accessible. additional_reference_ids: - PMID:27189942 - PMID:22284051 supported_by: - reference_id: PMID:27189942 supporting_text: EHD proteins have an EH domain that interacts with proteins containing an NPF motif - reference_id: PMID:27189942 supporting_text: EHD1 and EHD3 have 86% amino acid identity; they homo- and heterodimerize and partially co-localize to TRE - term: id: GO:0005768 label: endosome evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Endosome localization is supported and relevant to ANKFY1 function. action: ACCEPT reason: The original ANKHZN paper and later Rabankyrin-5 studies place the protein on endosomes, where it binds Rab5/PI3P and coordinates endocytic trafficking. additional_reference_ids: *id012 supported_by: - *id004 - *id003 - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:10940552 qualifier: located_in review: summary: Cytoplasmic localization is supported but is less informative than endosome-membrane localization. action: KEEP_AS_NON_CORE reason: ANKFY1 was initially described as a cytoplasmic protein and is present in soluble fractions, but the biologically informative location is its recruitment to PI3P/Rab5-positive endosomal membranes. additional_reference_ids: - PMID:10940552 - PMID:15328530 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id004 - *id008 - *id003 - term: id: GO:0005769 label: early endosome evidence_type: EXP original_reference_id: PMID:22284051 qualifier: located_in review: summary: Early endosome localization is supported by Rabankyrin-5 colocalization with Rab5/EEA1-positive compartments and later functional studies. action: ACCEPT reason: ANKFY1/Rabankyrin-5 localizes to early endosomes and its endosomal localization is required for endosomal fusion, retromer-related trafficking, and ATG2A recruitment during autophagy stimulation. additional_reference_ids: - PMID:15328530 - PMID:22284051 - PMID:29959197 - PMID:38622126 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id003 - *id005 - *id006 - *id007 - term: id: GO:0005769 label: early endosome evidence_type: EXP original_reference_id: PMID:29959197 qualifier: located_in review: summary: Early endosome localization is supported by Rabankyrin-5 colocalization with Rab5/EEA1-positive compartments and later functional studies. action: ACCEPT reason: ANKFY1/Rabankyrin-5 localizes to early endosomes and its endosomal localization is required for endosomal fusion, retromer-related trafficking, and ATG2A recruitment during autophagy stimulation. additional_reference_ids: - PMID:15328530 - PMID:22284051 - PMID:29959197 - PMID:38622126 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id003 - *id005 - *id006 - *id007 - term: id: GO:0010008 label: endosome membrane evidence_type: EXP original_reference_id: PMID:10940552 qualifier: located_in review: summary: Endosome membrane localization/activity is well supported for ANKFY1/Rabankyrin-5. action: ACCEPT reason: ANKFY1 is a FYVE-domain Rab5 effector that binds PI3P and localizes on early/endosomal membranes; this location is central to its endosomal trafficking and ATG2A-bridging roles. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id003 - *id009 - *id007 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9013438 qualifier: located_in review: summary: Endosome membrane localization/activity is well supported for ANKFY1/Rabankyrin-5. action: ACCEPT reason: ANKFY1 is a FYVE-domain Rab5 effector that binds PI3P and localizes on early/endosomal membranes; this location is central to its endosomal trafficking and ATG2A-bridging roles. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id003 - *id009 - *id007 - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:18570454 qualifier: located_in review: summary: Extracellular exosome detection comes from high-throughput proteomics and is not central to ANKFY1 function. action: KEEP_AS_NON_CORE reason: The exosome rows may reflect proteomic detection, but they do not explain the core Rab5/PI3P/endosomal trafficking and ATG2A autophagosome-assembly roles. additional_reference_ids: - PMID:15328530 - PMID:20562859 - PMID:38622126 supported_by: - *id003 - &id016 reference_id: PMID:20562859 supporting_text: depletion of ANKFY1 also led to increased autophagosomal number without blocking flux - *id007 - term: id: GO:0016197 label: endosomal transport evidence_type: IMP original_reference_id: PMID:24102721 qualifier: involved_in review: summary: Endosomal transport is supported by RhoD/PDGFR trafficking and the broader Rabankyrin-5 endosomal phenotype. action: ACCEPT reason: RhoD and Rabankyrin-5 coordinate Rab/Rho activities during internalization and trafficking of activated receptor cargo; this is consistent with the core endosomal transport function. additional_reference_ids: - PMID:24102721 - PMID:15328530 - PMID:22284051 supported_by: - &id017 reference_id: PMID:24102721 supporting_text: coordinating RhoD and Rab activities during internalization and trafficking of activated tyrosine kinase receptors - *id003 - *id002 - term: id: GO:0030904 label: retromer complex evidence_type: IDA original_reference_id: PMID:22284051 qualifier: colocalizes_with review: summary: Retromer complex colocalization is supported, but ANKFY1 is not established as a retromer complex subunit. action: KEEP_AS_NON_CORE reason: The qualifier is colocalizes_with, and the evidence shows interaction/colocalization with VPS26 and retromer distribution defects rather than stable retromer-complex membership. additional_reference_ids: - PMID:22284051 supported_by: - *id005 - *id002 - term: id: GO:0042147 label: retrograde transport, endosome to Golgi evidence_type: IMP original_reference_id: PMID:22284051 qualifier: involved_in review: summary: Endosome-to-Golgi retrograde transport is supported by Rank-5/retromer evidence. action: ACCEPT reason: Rank-5 interacts and colocalizes with retromer cargo-recognition components, and Rank-5 depletion impairs mannose 6-phosphate receptor retrieval from endosomes to the Golgi. additional_reference_ids: *id001 supported_by: - *id005 - *id002 - term: id: GO:0090160 label: Golgi to lysosome transport evidence_type: IMP original_reference_id: PMID:22284051 qualifier: involved_in review: summary: Golgi-to-lysosome/biosynthetic transport is supported as part of the Rank-5 retromer-trafficking phenotype. action: ACCEPT reason: The same Rank-5 depletion experiments that disrupt retromer distribution also affect biosynthetic transport, consistent with a role in endosome/Golgi/lysosome trafficking. additional_reference_ids: *id001 supported_by: - *id002 - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:15328530 qualifier: located_in review: summary: Early endosome localization is supported by Rabankyrin-5 colocalization with Rab5/EEA1-positive compartments and later functional studies. action: ACCEPT reason: ANKFY1/Rabankyrin-5 localizes to early endosomes and its endosomal localization is required for endosomal fusion, retromer-related trafficking, and ATG2A recruitment during autophagy stimulation. additional_reference_ids: - PMID:15328530 - PMID:22284051 - PMID:29959197 - PMID:38622126 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id003 - *id005 - *id006 - *id007 - term: id: GO:0031267 label: small GTPase binding evidence_type: IDA original_reference_id: PMID:15328530 qualifier: enables review: summary: Small GTPase binding is directly supported by Rab5 and RhoD/RAB-family interaction evidence. action: ACCEPT reason: Rabankyrin-5 was identified as a GTP-dependent Rab5 effector, and additional disease/trafficking work supports interaction with RAB5-regulatory machinery; this is a core molecular function. additional_reference_ids: - PMID:15328530 - PMID:24102721 - PMID:29959197 - file:human/ANKFY1/ANKFY1-uniprot.txt supported_by: - *id010 - *id013 - *id006 - term: id: GO:0034058 label: endosomal vesicle fusion evidence_type: IDA original_reference_id: PMID:15328530 qualifier: involved_in review: summary: Endosomal vesicle fusion is directly supported by the original Rabankyrin-5 functional study. action: ACCEPT reason: Rabankyrin-5 is a Rab5/PI3P effector that stimulates early-endosome fusion and affects endosomal vesicle dynamics. additional_reference_ids: - PMID:15328530 supported_by: - *id003 - reference_id: PMID:15328530 supporting_text: Rabankyrin-5 is a Rab5 effector required for the formation of macropinosomes - term: id: GO:0044354 label: macropinosome evidence_type: IDA original_reference_id: PMID:15328530 qualifier: located_in review: summary: Macropinosome localization is directly supported and relevant to the pinocytosis phenotype. action: ACCEPT reason: Rabankyrin-5 localizes to macropinosomes and its perturbation changes fluid-phase uptake. additional_reference_ids: - PMID:15328530 supported_by: - &id014 reference_id: PMID:15328530 supporting_text: Overexpression of Rabankyrin-5 increases the number of macropinosomes and stimulates fluid-phase uptake, whereas its downregulation inhibits these processes - term: id: GO:0048549 label: positive regulation of pinocytosis evidence_type: IDA original_reference_id: PMID:15328530 qualifier: involved_in review: summary: Positive regulation of pinocytosis is directly supported. action: ACCEPT reason: Overexpression and depletion experiments show that Rabankyrin-5 promotes fluid-phase/macropinocytic uptake, including apical non-clathrin-mediated uptake in polarized cells. additional_reference_ids: - PMID:15328530 supported_by: - *id014 - reference_id: PMID:15328530 supporting_text: specifically stimulates apical, non-clathrin-mediated fluid-phase endocytosis - term: id: GO:1901981 label: phosphatidylinositol phosphate binding evidence_type: IDA original_reference_id: PMID:15328530 qualifier: enables review: summary: Phosphatidylinositol phosphate binding is a core ANKFY1 molecular function. action: ACCEPT reason: ANKFY1/Rabankyrin-5 binds PI3P via its FYVE domain; this lipid-binding activity explains endosomal recruitment and is required for ATG2A-mediated lipid-transfer enhancement. additional_reference_ids: - PMID:15328530 - PMID:38622126 supported_by: - *id009 - *id015 - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Extracellular exosome detection comes from high-throughput proteomics and is not central to ANKFY1 function. action: KEEP_AS_NON_CORE reason: The exosome rows may reflect proteomic detection, but they do not explain the core Rab5/PI3P/endosomal trafficking and ATG2A autophagosome-assembly roles. additional_reference_ids: - PMID:15328530 - PMID:20562859 - PMID:38622126 supported_by: - *id003 - *id016 - *id007 - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Lysosomal membrane detection is plausible but high-throughput and not core. action: KEEP_AS_NON_CORE reason: The dominant evidence places ANKFY1 on early/endosomal membranes; lysosomal-membrane proteomic detection is peripheral and should not drive the core function summary. additional_reference_ids: - PMID:15328530 - PMID:38622126 supported_by: - *id003 - *id007 - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:10940552 qualifier: located_in review: summary: Generic membrane localization is supported but too broad to represent the core location. action: KEEP_AS_NON_CORE reason: Membrane association is real, but the more informative annotation is endosome membrane/early endosome, where ANKFY1 binds PI3P and functions with Rab5 and ATG2A. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id008 - *id003 - *id007 - term: id: GO:0010008 label: endosome membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Endosome membrane localization/activity is well supported for ANKFY1/Rabankyrin-5. action: ACCEPT reason: ANKFY1 is a FYVE-domain Rab5 effector that binds PI3P and localizes on early/endosomal membranes; this location is central to its endosomal trafficking and ATG2A-bridging roles. additional_reference_ids: - PMID:15328530 - PMID:10940552 - file:human/ANKFY1/ANKFY1-uniprot.txt - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md supported_by: - *id003 - *id009 - *id007 - term: id: GO:0000045 label: autophagosome assembly evidence_type: IMP original_reference_id: PMID:38622126 qualifier: involved_in review: summary: ANKFY1 should be added to autophagosome assembly for its ATG2A-dependent endosome-to-phagophore lipid-transfer role. action: NEW reason: ANKFY1 depletion impairs autophagosome growth, reduces autophagy flux, and phenocopies ATG2A/B depletion; in vitro ANKFY1 enhances ATG2A-mediated lipid transfer between PI3P-containing membranes. GO:0000045 is the conservative process term for this phagophore-growth/autophagosome-completion role. additional_reference_ids: - PMID:38622126 - file:human/ANKFY1/ANKFY1-notes.md - file:human/ANKFY1/ANKFY1-deep-research-falcon.md supported_by: - &id018 reference_id: PMID:38622126 supporting_text: identified a new ATG2A-binding protein, ANKFY1 - &id019 reference_id: PMID:38622126 supporting_text: Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux - *id015 - *id007 - reference_id: file:human/ANKFY1/ANKFY1-deep-research-falcon.md supporting_text: A 2024 study identified ANKFY1 as an ATG2A-binding endosomal factor that bridges endosomes and phagophores, promoting ATG2A-mediated lipid transfer for phagophore growth references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10940552 title: Characterization and chromosomal mapping of a novel human gene, ANKHZN. findings: [] - id: PMID:15328530 title: The Rab5 effector Rabankyrin-5 regulates and coordinates different endocytic mechanisms. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:18570454 title: Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: [] - id: PMID:22284051 title: Rabankyrin-5 interacts with EHD1 and Vps26 to regulate endocytic trafficking and retromer function. findings: [] - id: PMID:24102721 title: RhoD binds the Rab5 effector Rabankyrin-5 and has a role in trafficking of the platelet-derived growth factor receptor. findings: [] - id: PMID:27189942 title: EHD3 Protein Is Required for Tubular Recycling Endosome Stabilization, and an Asparagine-Glutamic Acid Residue Pair within Its Eps15 Homology (EH) Domain Dictates Its Selective Binding to NPF Peptides. findings: [] - id: PMID:29959197 title: GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome. findings: [] - id: Reactome:R-HSA-9013438 title: RHOD binds effectors at the endosome membrane findings: [] - id: PMID:38622126 title: ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores. findings: - statement: ANKFY1 binds ATG2A during autophagy stimulation and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. - statement: ANKFY1 depletion impairs autophagosome growth and reduces autophagy flux. - id: file:human/ANKFY1/ANKFY1-uniprot.txt title: UniProtKB record for human ANKFY1/Rabankyrin-5 findings: - statement: UniProt summarizes ANKFY1 as a Rab5 effector involved in endosomal trafficking, macropinocytosis, receptor internalization, retromer-mediated transport, and podocyte migration. - id: file:human/ANKFY1/ANKFY1-notes.md title: ANKFY1 review notes for Proteostasis PN assessment findings: - statement: The PN Cul3 substrate-receptor projection to GO:1990756 is not supported by ANKFY1-specific evidence. - statement: ANKFY1 is proteostasis-relevant through endosome-autophagosome lipid transfer rather than validated ubiquitin-like ligase-substrate adaptor activity. - id: file:human/ANKFY1/ANKFY1-deep-research-falcon.md title: Falcon deep research report for human ANKFY1 findings: - statement: The Falcon report summarizes ANKFY1 as a Rab5/PI3P endosomal scaffold with recent ATG2A-mediated autophagy evidence. - id: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projected annotations report findings: - statement: The report projects GO:1990756 to ANKFY1 from the Cul3 substrate receptor PN group. core_functions: - description: ANKFY1 is a Rab5/PI3P-positive endosomal effector that coordinates early endosome fusion, macropinocytosis, endosomal transport, and retromer-associated endosome-to-Golgi and Golgi-to-lysosome trafficking. molecular_function: id: GO:0031267 label: small GTPase binding directly_involved_in: - id: GO:0034058 label: endosomal vesicle fusion - id: GO:0048549 label: positive regulation of pinocytosis - id: GO:0016197 label: endosomal transport - id: GO:0042147 label: retrograde transport, endosome to Golgi - id: GO:0090160 label: Golgi to lysosome transport locations: - id: GO:0010008 label: endosome membrane - id: GO:0005769 label: early endosome - id: GO:0044354 label: macropinosome supported_by: - *id010 - *id009 - *id014 - *id002 - *id017 - description: ANKFY1 binds PI3P-rich endosomal membranes through its FYVE domain and promotes ATG2A-mediated lipid transfer from endosomes to phagophores, supporting autophagosome growth and completion during autophagy induction. molecular_function: id: GO:1901981 label: phosphatidylinositol phosphate binding directly_involved_in: - id: GO:0000045 label: autophagosome assembly locations: - id: GO:0010008 label: endosome membrane - id: GO:0005769 label: early endosome supported_by: - *id018 - *id019 - *id015 - *id007 - reference_id: file:human/ANKFY1/ANKFY1-notes.md supporting_text: ANKFY1 also has direct autophagy-relevant evidence proposed_new_terms: [] suggested_questions: - question: Is there direct experimental evidence that ANKFY1 binds CUL3 or functions as a CRL3/ubiquitin-like ligase substrate adaptor in cells? experts: - GO ubiquitin-proteasome curators - Proteostasis PN curators - question: Should ANKFY1 autophagy annotation be limited to autophagosome assembly, or should a more specific future term capture endosome-to-phagophore lipid-transfer bridging by ATG2A adaptors? experts: - GO autophagy editors suggested_experiments: - experiment_type: Endogenous CUL3 complex and ubiquitination assay hypothesis: ANKFY1 does not function as a CRL3 substrate receptor unless it shows endogenous CUL3 complex membership and substrate-dependent ubiquitination activity. description: Test endogenous ANKFY1-CUL3 binding by reciprocal co-immunoprecipitation or proximity labeling, identify candidate substrates, and determine whether ANKFY1 loss changes CUL3-dependent ubiquitination of those substrates. - experiment_type: ANKFY1 autophagy rescue assay hypothesis: FYVE-dependent endosomal recruitment and ATG2A binding are required for ANKFY1 support of phagophore growth. description: Rescue ANKFY1 knockout cells with wild-type, FYVE-deleted, and ATG2A-binding-defective ANKFY1 variants, then assay Halo-LC3 autophagosome completion, LC3 flux, WIPI2/LC3 phagophore PI3P, and in vitro ATG2A lipid transfer.