{"gene":"FHIP2A","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2021,"finding":"FHIP2A forms a FTS-Hook2-FHIP2A complex (FHF complex) that associates with Rab1A-tagged ER-to-Golgi cargos and is involved in the motility of Rab1A tubules, linking cytoplasmic dynein-1 to ER-to-Golgi cargo transport.","method":"Proteomic interactome mapping, live-cell imaging, biochemical co-purification, single-molecule in vitro reconstitution assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (proteomics, live imaging, biochemical reconstitution) in single rigorous study establishing complex composition, cargo identity, and motility function","pmids":["34882091"],"is_preprint":false},{"year":2026,"finding":"FHIP2A interacts with the small GTPase Rab1 (Rab1A/Rab1B) in a membrane-dependent manner, and this interaction recruits dynein to the ER-Golgi intermediate compartment (ERGIC); the interaction could only be detected in the presence of membranes, explaining why it was missed by conventional methods.","method":"MitoID proximity biotinylation interactome, in vitro binding validation, membrane-dependent interaction assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proximity biotinylation plus in vitro validation with membrane-dependency requirement; single lab but multiple orthogonal approaches","pmids":["41493270"],"is_preprint":false}],"current_model":"FHIP2A assembles into a FTS-Hook2-FHIP2A complex that links cytoplasmic dynein-1 to ER-to-Golgi cargos by directly interacting with GTP-bound Rab1A in a membrane-dependent manner, thereby recruiting dynein to the ERGIC and driving Rab1A tubule motility."},"narrative":{"mechanistic_narrative":"FHIP2A is an adaptor subunit that couples cytoplasmic dynein-1 to ER-to-Golgi membrane cargo, functioning as part of an FTS-Hook2-FHIP2A (FHF) complex that associates with Rab1A-marked ER-to-Golgi cargos and drives the motility of Rab1A tubules [PMID:34882091]. FHIP2A engages the small GTPase Rab1 (Rab1A/Rab1B) in a strictly membrane-dependent manner, and this interaction recruits dynein to the ER-Golgi intermediate compartment (ERGIC), establishing the molecular link between a membrane-bound Rab GTPase and the dynein transport machinery [PMID:41493270]. Beyond its role as a Rab1-dependent dynein adaptor in ER-to-Golgi transport, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Established that FHIP2A is a constituent of the FHF complex that physically links dynein-1 to ER-to-Golgi cargo, answering how this transport machinery couples to its membrane cargo and identifying Rab1A tubules as the cargo whose motility it controls.","evidence":"Proteomic interactome mapping, live-cell imaging, and single-molecule in vitro reconstitution","pmids":["34882091"],"confidence":"High","gaps":["Direct molecular contact between FHIP2A and the cargo was not resolved","Mechanism of dynein activation by the complex not detailed at residue level"]},{"year":2026,"claim":"Resolved how FHIP2A connects to cargo by showing it binds Rab1 only in the presence of membranes, explaining why the interaction was missed by conventional assays and defining the ERGIC as the site of dynein recruitment.","evidence":"MitoID proximity biotinylation interactome with in vitro binding validation and a membrane-dependent interaction assay","pmids":["41493270"],"confidence":"High","gaps":["Structural basis of the membrane-dependent Rab1-FHIP2A interface unknown","Whether GTP/GDP state of Rab1 alone is sufficient versus additional membrane lipid requirements not fully dissected","Functional consequences of disrupting the interaction in vivo not characterized"]},{"year":null,"claim":"How FHIP2A-mediated dynein recruitment is regulated and integrated with other ER-to-Golgi trafficking events remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the FHF-Rab1-membrane assembly","Regulatory inputs controlling FHIP2A engagement unknown","Tissue/physiological roles not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]}],"complexes":["FHF complex (FTS-Hook2-FHIP2A)"],"partners":["HOOK2","FTS","RAB1A","RAB1B","DYNC1H1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5W0V3","full_name":"FHF complex subunit HOOK interacting protein 2A","aliases":[],"length_aa":765,"mass_kda":86.6,"function":"Required for proper functioning of the nervous system","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5W0V3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FHIP2A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FHIP2A","total_profiled":1310},"omim":[{"mim_id":"620230","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2B; FHIP2B","url":"https://www.omim.org/entry/620230"},{"mim_id":"620229","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 1B; FHIP1B","url":"https://www.omim.org/entry/620229"},{"mim_id":"619625","title":"CHROMOSOME 11 OPEN READING FRAME 58; C11ORF58","url":"https://www.omim.org/entry/619625"},{"mim_id":"617312","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2A; FHIP2A","url":"https://www.omim.org/entry/617312"},{"mim_id":"607825","title":"HOOK MICROTUBULE TETHERING PROTEIN 3; HOOK3","url":"https://www.omim.org/entry/607825"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":50.3}],"url":"https://www.proteinatlas.org/search/FHIP2A"},"hgnc":{"alias_symbol":["bA106M7.3"],"prev_symbol":["KIAA1600","FAM160B1"]},"alphafold":{"accession":"Q5W0V3","domains":[{"cath_id":"-","chopping":"292-495","consensus_level":"medium","plddt":93.6135,"start":292,"end":495},{"cath_id":"-","chopping":"566-764","consensus_level":"high","plddt":91.7745,"start":566,"end":764},{"cath_id":"1.20.1050","chopping":"2-139","consensus_level":"high","plddt":86.5717,"start":2,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5W0V3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5W0V3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5W0V3-F1-predicted_aligned_error_v6.png","plddt_mean":79.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FHIP2A","jax_strain_url":"https://www.jax.org/strain/search?query=FHIP2A"},"sequence":{"accession":"Q5W0V3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5W0V3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5W0V3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5W0V3"}},"corpus_meta":[{"pmid":"27431290","id":"PMC_27431290","title":"Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27431290","citation_count":202,"is_preprint":false},{"pmid":"34882091","id":"PMC_34882091","title":"Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34882091","citation_count":37,"is_preprint":false},{"pmid":"28639078","id":"PMC_28639078","title":"A Genome-wide Expression Association Analysis Identifies Genes and Pathways Associated with Amyotrophic Lateral Sclerosis.","date":"2017","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28639078","citation_count":29,"is_preprint":false},{"pmid":"26668583","id":"PMC_26668583","title":"A susceptibility locus rs7099208 is associated with non-obstructive azoospermia via reduction in the expression of FAM160B1.","date":"2015","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/26668583","citation_count":3,"is_preprint":false},{"pmid":"31353455","id":"PMC_31353455","title":"FAM160B1 deficit associated with microcephaly, severe intellectual disability, ataxia, behavioral abnormalities and speech problems.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31353455","citation_count":2,"is_preprint":false},{"pmid":"41493270","id":"PMC_41493270","title":"A Rab1 interactome illuminates a dual role in autophagy and membrane trafficking.","date":"2026","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41493270","citation_count":1,"is_preprint":false},{"pmid":"26673547","id":"PMC_26673547","title":"Erratum: A susceptibility locus rs7099208 is associated with non-obstructive azoospermia via reduction in the expression of FAM160B1.","date":"2015","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/26673547","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5343,"output_tokens":577,"usd":0.012342,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6884,"output_tokens":1290,"usd":0.033335,"stage2_stop_reason":"end_turn"},"total_usd":0.045677,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"FHIP2A forms a FTS-Hook2-FHIP2A complex (FHF complex) that associates with Rab1A-tagged ER-to-Golgi cargos and is involved in the motility of Rab1A tubules, linking cytoplasmic dynein-1 to ER-to-Golgi cargo transport.\",\n      \"method\": \"Proteomic interactome mapping, live-cell imaging, biochemical co-purification, single-molecule in vitro reconstitution assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (proteomics, live imaging, biochemical reconstitution) in single rigorous study establishing complex composition, cargo identity, and motility function\",\n      \"pmids\": [\"34882091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FHIP2A interacts with the small GTPase Rab1 (Rab1A/Rab1B) in a membrane-dependent manner, and this interaction recruits dynein to the ER-Golgi intermediate compartment (ERGIC); the interaction could only be detected in the presence of membranes, explaining why it was missed by conventional methods.\",\n      \"method\": \"MitoID proximity biotinylation interactome, in vitro binding validation, membrane-dependent interaction assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proximity biotinylation plus in vitro validation with membrane-dependency requirement; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"41493270\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FHIP2A assembles into a FTS-Hook2-FHIP2A complex that links cytoplasmic dynein-1 to ER-to-Golgi cargos by directly interacting with GTP-bound Rab1A in a membrane-dependent manner, thereby recruiting dynein to the ERGIC and driving Rab1A tubule motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FHIP2A is an adaptor subunit that couples cytoplasmic dynein-1 to ER-to-Golgi membrane cargo, functioning as part of an FTS-Hook2-FHIP2A (FHF) complex that associates with Rab1A-marked ER-to-Golgi cargos and drives the motility of Rab1A tubules [#0]. FHIP2A engages the small GTPase Rab1 (Rab1A/Rab1B) in a strictly membrane-dependent manner, and this interaction recruits dynein to the ER-Golgi intermediate compartment (ERGIC), establishing the molecular link between a membrane-bound Rab GTPase and the dynein transport machinery [#1]. Beyond its role as a Rab1-dependent dynein adaptor in ER-to-Golgi transport, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that FHIP2A is a constituent of the FHF complex that physically links dynein-1 to ER-to-Golgi cargo, answering how this transport machinery couples to its membrane cargo and identifying Rab1A tubules as the cargo whose motility it controls.\",\n      \"evidence\": \"Proteomic interactome mapping, live-cell imaging, and single-molecule in vitro reconstitution\",\n      \"pmids\": [\"34882091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular contact between FHIP2A and the cargo was not resolved\",\n        \"Mechanism of dynein activation by the complex not detailed at residue level\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved how FHIP2A connects to cargo by showing it binds Rab1 only in the presence of membranes, explaining why the interaction was missed by conventional assays and defining the ERGIC as the site of dynein recruitment.\",\n      \"evidence\": \"MitoID proximity biotinylation interactome with in vitro binding validation and a membrane-dependent interaction assay\",\n      \"pmids\": [\"41493270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the membrane-dependent Rab1-FHIP2A interface unknown\",\n        \"Whether GTP/GDP state of Rab1 alone is sufficient versus additional membrane lipid requirements not fully dissected\",\n        \"Functional consequences of disrupting the interaction in vivo not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FHIP2A-mediated dynein recruitment is regulated and integrated with other ER-to-Golgi trafficking events remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the FHF-Rab1-membrane assembly\",\n        \"Regulatory inputs controlling FHIP2A engagement unknown\",\n        \"Tissue/physiological roles not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005793\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"FHF complex (FTS-Hook2-FHIP2A)\"],\n    \"partners\": [\"HOOK2\", \"FTS\", \"RAB1A\", \"RAB1B\", \"DYNC1H1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}