Affinage

CIB3

Calcium and integrin-binding family member 3 · UniProt Q96Q77

Length
187 aa
Mass
21.8 kDa
Annotated
2026-06-09
10 papers in source corpus 2 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/3 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2021 High

    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

    PMID:34089643

    Open questions at the time
    • Functional necessity of CIB3 specifically (versus CIB2 redundancy) in cochlear hair cells not isolated
    • Whether CIB3 modulates channel gating or only assembly/trafficking unresolved
  2. 2023 High

    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

    PMID:37001993

    Open questions at the time
    • Mechanism of extrastriolar-specific stereocilia maintenance unknown
    • Molecular basis for the functional division of labor between CIB2 and CIB3 not determined
  3. 2024 Low

    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)

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CIB3 mechanistically contributes to channel gating, force transmission, or stereocilia maintenance—and whether its non-hair-cell roles are physiologically real—remains open.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 1
Partners
CIB2TMC1TMC2
Complex memberships
MET channel complex (TMC1/2)

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. X-ray crystallography (co-crystal structure of TMC1 CIB-binding domain with CIB3), functional studies in mice (knockout), structural comparison with KChIP-Kv4 complex Neuron High 34089643
2023 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. Single and double knockout mouse models (Cib2 KO, Cib3 KO, Cib2/Cib3 double KO), MET current electrophysiology, fluorescence microscopy of stereocilia The Journal of neuroscience High 37001993
2024 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. Colocalization imaging in cultured cells, in vitro complex formation with a TMC5 fragment, homology/AlphaFold2 modeling bioRxivpreprint Low

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Plus end-specific depolymerase activity of Kip3, a kinesin-8 protein, explains its role in positioning the yeast mitotic spindle. Nature cell biology 263 16906148
1997 Kinesin-related KIP3 of Saccharomyces cerevisiae is required for a distinct step in nuclear migration. The Journal of cell biology 154 9281581
2021 CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. Neuron 66 34089643
2010 Kip3, the yeast kinesin-8, is required for clustering of kinetochores at metaphase. Cell cycle (Georgetown, Tex.) 57 20603597
2004 The Kip3-like kinesin KipB moves along microtubules and determines spindle position during synchronized mitoses in Aspergillus nidulans hyphae. Eukaryotic cell 44 15189985
2014 The kinesin-8 Kip3 scales anaphase spindle length by suppression of midzone microtubule polymerization. The Journal of cell biology 36 24616221
2023 CIB2 and CIB3 Regulate Stereocilia Maintenance and Mechanoelectrical Transduction in Mouse Vestibular Hair Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 37001993
2018 Three-Dimensional Optical Tweezers Tracking Resolves Random Sideward Steps of the Kinesin-8 Kip3. Biophysical journal 13 30360926
2020 The Kinesin-8 Kip3 Depolymerizes Microtubules with a Collective Force-Dependent Mechanism. Biophysical journal 12 32229316
2018 Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly. Molecular biology of the cell 7 29874146

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