{"gene":"CIB3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2021,"finding":"CIB3 is an auxiliary subunit of the mechanotransduction (MET) channel in inner-ear hair cells. CIB3 binds directly to TMC1/2 through a domain flanked by transmembrane domains 2 and 3 of TMC1/2, mediated via a conserved hydrophobic groove on CIB3, as revealed by co-crystal structure of the CIB-binding domain of TMC1 with CIB3. CIB3 is structurally similar to KChIP proteins (auxiliary subunits of Kv4 channels), and can functionally substitute for CIB2 in cochlear hair cells.","method":"X-ray crystallography (co-crystal structure of TMC1 CIB-binding domain with CIB3), functional studies in mice (knockout), structural comparison with KChIP-Kv4 complex","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure with mutagenesis-informed analysis plus functional mouse knockout studies, multiple orthogonal methods in single rigorous study","pmids":["34089643"],"is_preprint":false},{"year":2023,"finding":"CIB3 is required for mechanoelectrical transduction (MET) in vestibular hair cells (VHCs): Cib2/Cib3 double knockout completely abolishes MET currents in VHCs. CIB3 also regulates stereocilia maintenance specifically in extrastriolar VHCs in a non-redundant manner with CIB2, as demonstrated by single and double knockout mice.","method":"Single and double knockout mouse models (Cib2 KO, Cib3 KO, Cib2/Cib3 double KO), MET current electrophysiology, fluorescence microscopy of stereocilia","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (MET current abolition, stereocilia defects), multiple genotypes and orthogonal readouts","pmids":["37001993"],"is_preprint":false},{"year":2024,"finding":"CIB3 localizes to microvillar tips in intestinal epithelial cells and forms a complex with TMC5 in vitro, suggesting CIB3 participates in a mechanosensitive complex at microvillar tips analogous to its role with TMC1/2 in stereocilia.","method":"Colocalization imaging in cultured cells, in vitro complex formation with a TMC5 fragment, homology/AlphaFold2 modeling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single pulldown/colocalization method for CIB3-TMC5 interaction; functional role in intestinal microvilli not experimentally confirmed","pmids":[],"is_preprint":true}],"current_model":"CIB3 (Calcium and Integrin Binding protein 3) is an auxiliary subunit of the mechanotransduction (MET) channel in inner-ear hair cells: it directly binds TMC1/2 through a conserved hydrophobic groove (structurally analogous to KChIP binding of Kv4 channels), can functionally substitute for CIB2 in cochlear hair cells, and acts redundantly with CIB2 to sustain MET currents and maintain stereocilia in vestibular hair cells, with CIB3 being specifically required in the extrastriolar region."},"narrative":{"mechanistic_narrative":"CIB3 is an auxiliary subunit of the mechanotransduction (MET) channel complex in inner-ear hair cells, where it directly binds the pore-forming subunits TMC1 and TMC2 to support sensory mechanotransduction [PMID:34089643]. The interaction is structurally defined: a co-crystal structure shows CIB3 engaging a TMC1/2 region flanked by transmembrane domains 2 and 3 through a conserved hydrophobic groove, an architecture analogous to KChIP binding of Kv4 channels, and CIB3 can functionally substitute for its paralog CIB2 in cochlear hair cells [PMID:34089643]. In vestibular hair cells CIB3 acts redundantly with CIB2 to sustain MET currents—Cib2/Cib3 double knockout abolishes vestibular MET currents—while playing a non-redundant role in maintaining stereocilia specifically in the extrastriolar region [PMID:37001993]. Beyond its role at hair-cell stereocilia, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Established the molecular and structural basis for CIB3 as a MET channel auxiliary subunit, answering how CIB proteins physically engage the TMC pore-forming subunits in hair cells.","evidence":"co-crystal structure of the TMC1 CIB-binding domain with CIB3, mouse knockout functional studies, and structural comparison to the KChIP-Kv4 complex","pmids":["34089643"],"confidence":"High","gaps":["Functional necessity of CIB3 specifically (versus CIB2 redundancy) in cochlear hair cells not isolated","Whether CIB3 modulates channel gating or only assembly/trafficking unresolved"]},{"year":2023,"claim":"Defined the in vivo requirement for CIB3 in vestibular mechanotransduction, distinguishing redundant from non-redundant roles relative to CIB2.","evidence":"single and double Cib2/Cib3 knockout mice with MET current electrophysiology and stereocilia imaging in vestibular hair cells","pmids":["37001993"],"confidence":"High","gaps":["Mechanism of extrastriolar-specific stereocilia maintenance unknown","Molecular basis for the functional division of labor between CIB2 and CIB3 not determined"]},{"year":2024,"claim":"Raised the possibility that CIB3 function extends beyond the ear into intestinal microvillar mechanosensitive complexes via a TMC5 partner.","evidence":"colocalization at microvillar tips in cultured cells, in vitro complex formation with a TMC5 fragment, and AlphaFold2 modeling (preprint)","pmids":[],"confidence":"Low","gaps":["Single-lab pulldown/colocalization without reciprocal or in vivo validation","Functional role of CIB3 in intestinal microvilli not experimentally tested","Physiological relevance of the CIB3-TMC5 interaction unestablished"]},{"year":null,"claim":"How CIB3 mechanistically contributes to channel gating, force transmission, or stereocilia maintenance—and whether its non-hair-cell roles are physiologically real—remains open.","evidence":"no direct evidence in the available corpus","pmids":[],"confidence":"Low","gaps":["No data on whether CIB3 alters MET channel conductance or gating kinetics","Calcium-dependence of CIB3 function not characterized in the timeline","Tissue distribution and in vivo function outside the inner ear unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["MET channel complex (TMC1/2)"],"partners":["TMC1","TMC2","CIB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96Q77","full_name":"Calcium and integrin-binding family member 3","aliases":["Kinase-interacting protein 3","KIP 3"],"length_aa":187,"mass_kda":21.8,"function":"Acts a an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells (By similarity). Plays a role in regulating hair cell MET channel localization and function (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96Q77/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIB3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIB3","total_profiled":1310},"omim":[{"mim_id":"610645","title":"CALCIUM- AND INTEGRIN-BINDING PROTEIN 3; CIB3","url":"https://www.omim.org/entry/610645"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"bone marrow","ntpm":1.2}],"url":"https://www.proteinatlas.org/search/CIB3"},"hgnc":{"alias_symbol":["KIP3"],"prev_symbol":[]},"alphafold":{"accession":"Q96Q77","domains":[{"cath_id":"1.10.238.10","chopping":"11-99","consensus_level":"high","plddt":92.2157,"start":11,"end":99},{"cath_id":"1.10.238.10","chopping":"105-183","consensus_level":"high","plddt":87.9924,"start":105,"end":183}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q77","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q77-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q77-F1-predicted_aligned_error_v6.png","plddt_mean":85.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIB3","jax_strain_url":"https://www.jax.org/strain/search?query=CIB3"},"sequence":{"accession":"Q96Q77","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q77.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q77/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q77"}},"corpus_meta":[{"pmid":"16906148","id":"PMC_16906148","title":"Plus end-specific depolymerase activity of Kip3, a kinesin-8 protein, explains its role in positioning the yeast mitotic spindle.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16906148","citation_count":263,"is_preprint":false},{"pmid":"9281581","id":"PMC_9281581","title":"Kinesin-related KIP3 of Saccharomyces cerevisiae is required for a distinct step in nuclear migration.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9281581","citation_count":154,"is_preprint":false},{"pmid":"34089643","id":"PMC_34089643","title":"CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells.","date":"2021","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/34089643","citation_count":66,"is_preprint":false},{"pmid":"20603597","id":"PMC_20603597","title":"Kip3, the yeast kinesin-8, is required for clustering of kinetochores at metaphase.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20603597","citation_count":57,"is_preprint":false},{"pmid":"15189985","id":"PMC_15189985","title":"The Kip3-like kinesin KipB moves along microtubules and determines spindle position during synchronized mitoses in Aspergillus nidulans hyphae.","date":"2004","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/15189985","citation_count":44,"is_preprint":false},{"pmid":"24616221","id":"PMC_24616221","title":"The kinesin-8 Kip3 scales anaphase spindle length by suppression of midzone microtubule polymerization.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24616221","citation_count":36,"is_preprint":false},{"pmid":"37001993","id":"PMC_37001993","title":"CIB2 and CIB3 Regulate Stereocilia Maintenance and Mechanoelectrical Transduction in Mouse Vestibular Hair Cells.","date":"2023","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37001993","citation_count":18,"is_preprint":false},{"pmid":"30360926","id":"PMC_30360926","title":"Three-Dimensional Optical Tweezers Tracking Resolves Random Sideward Steps of the Kinesin-8 Kip3.","date":"2018","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/30360926","citation_count":13,"is_preprint":false},{"pmid":"32229316","id":"PMC_32229316","title":"The Kinesin-8 Kip3 Depolymerizes Microtubules with a Collective Force-Dependent Mechanism.","date":"2020","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32229316","citation_count":12,"is_preprint":false},{"pmid":"29874146","id":"PMC_29874146","title":"Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29874146","citation_count":7,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.27.635192","title":"Kinesin-8/Kip3 requires beta tubulin tail for depolymerase activity","date":"2025-01-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.27.635192","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.22.609173","title":"Transmembrane channel-like 4 and 5 proteins at microvillar tips are potential ion channels and lipid scramblases","date":"2024-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.22.609173","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.05.611543","title":"Kinesin-8 motors dimerize by folding their proximal tail domain into a compact helical bundle","date":"2024-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.05.611543","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8191,"output_tokens":965,"usd":0.019524,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7420,"output_tokens":1576,"usd":0.03825,"stage2_stop_reason":"end_turn"},"total_usd":0.057774,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"CIB3 is an auxiliary subunit of the mechanotransduction (MET) channel in inner-ear hair cells. CIB3 binds directly to TMC1/2 through a domain flanked by transmembrane domains 2 and 3 of TMC1/2, mediated via a conserved hydrophobic groove on CIB3, as revealed by co-crystal structure of the CIB-binding domain of TMC1 with CIB3. CIB3 is structurally similar to KChIP proteins (auxiliary subunits of Kv4 channels), and can functionally substitute for CIB2 in cochlear hair cells.\",\n      \"method\": \"X-ray crystallography (co-crystal structure of TMC1 CIB-binding domain with CIB3), functional studies in mice (knockout), structural comparison with KChIP-Kv4 complex\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure with mutagenesis-informed analysis plus functional mouse knockout studies, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34089643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIB3 is required for mechanoelectrical transduction (MET) in vestibular hair cells (VHCs): Cib2/Cib3 double knockout completely abolishes MET currents in VHCs. CIB3 also regulates stereocilia maintenance specifically in extrastriolar VHCs in a non-redundant manner with CIB2, as demonstrated by single and double knockout mice.\",\n      \"method\": \"Single and double knockout mouse models (Cib2 KO, Cib3 KO, Cib2/Cib3 double KO), MET current electrophysiology, fluorescence microscopy of stereocilia\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (MET current abolition, stereocilia defects), multiple genotypes and orthogonal readouts\",\n      \"pmids\": [\"37001993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CIB3 localizes to microvillar tips in intestinal epithelial cells and forms a complex with TMC5 in vitro, suggesting CIB3 participates in a mechanosensitive complex at microvillar tips analogous to its role with TMC1/2 in stereocilia.\",\n      \"method\": \"Colocalization imaging in cultured cells, in vitro complex formation with a TMC5 fragment, homology/AlphaFold2 modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single pulldown/colocalization method for CIB3-TMC5 interaction; functional role in intestinal microvilli not experimentally confirmed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CIB3 (Calcium and Integrin Binding protein 3) is an auxiliary subunit of the mechanotransduction (MET) channel in inner-ear hair cells: it directly binds TMC1/2 through a conserved hydrophobic groove (structurally analogous to KChIP binding of Kv4 channels), can functionally substitute for CIB2 in cochlear hair cells, and acts redundantly with CIB2 to sustain MET currents and maintain stereocilia in vestibular hair cells, with CIB3 being specifically required in the extrastriolar region.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIB3 is an auxiliary subunit of the mechanotransduction (MET) channel complex in inner-ear hair cells, where it directly binds the pore-forming subunits TMC1 and TMC2 to support sensory mechanotransduction [#0]. The interaction is structurally defined: a co-crystal structure shows CIB3 engaging a TMC1/2 region flanked by transmembrane domains 2 and 3 through a conserved hydrophobic groove, an architecture analogous to KChIP binding of Kv4 channels, and CIB3 can functionally substitute for its paralog CIB2 in cochlear hair cells [#0]. In vestibular hair cells CIB3 acts redundantly with CIB2 to sustain MET currents—Cib2/Cib3 double knockout abolishes vestibular MET currents—while playing a non-redundant role in maintaining stereocilia specifically in the extrastriolar region [#1]. Beyond its role at hair-cell stereocilia, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the molecular and structural basis for CIB3 as a MET channel auxiliary subunit, answering how CIB proteins physically engage the TMC pore-forming subunits in hair cells.\",\n      \"evidence\": \"co-crystal structure of the TMC1 CIB-binding domain with CIB3, mouse knockout functional studies, and structural comparison to the KChIP-Kv4 complex\",\n      \"pmids\": [\"34089643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional necessity of CIB3 specifically (versus CIB2 redundancy) in cochlear hair cells not isolated\",\n        \"Whether CIB3 modulates channel gating or only assembly/trafficking unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the in vivo requirement for CIB3 in vestibular mechanotransduction, distinguishing redundant from non-redundant roles relative to CIB2.\",\n      \"evidence\": \"single and double Cib2/Cib3 knockout mice with MET current electrophysiology and stereocilia imaging in vestibular hair cells\",\n      \"pmids\": [\"37001993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of extrastriolar-specific stereocilia maintenance unknown\",\n        \"Molecular basis for the functional division of labor between CIB2 and CIB3 not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Raised the possibility that CIB3 function extends beyond the ear into intestinal microvillar mechanosensitive complexes via a TMC5 partner.\",\n      \"evidence\": \"colocalization at microvillar tips in cultured cells, in vitro complex formation with a TMC5 fragment, and AlphaFold2 modeling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-lab pulldown/colocalization without reciprocal or in vivo validation\",\n        \"Functional role of CIB3 in intestinal microvilli not experimentally tested\",\n        \"Physiological relevance of the CIB3-TMC5 interaction unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CIB3 mechanistically contributes to channel gating, force transmission, or stereocilia maintenance—and whether its non-hair-cell roles are physiologically real—remains open.\",\n      \"evidence\": \"no direct evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No data on whether CIB3 alters MET channel conductance or gating kinetics\",\n        \"Calcium-dependence of CIB3 function not characterized in the timeline\",\n        \"Tissue distribution and in vivo function outside the inner ear unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"MET channel complex (TMC1/2)\"],\n    \"partners\": [\"TMC1\", \"TMC2\", \"CIB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}