Affinage

CIB3

Calcium and integrin-binding family member 3 · UniProt Q96Q77

Length
187 aa
Mass
21.8 kDa
Annotated
2026-04-28
11 papers in source corpus 3 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIB3 is an auxiliary subunit of the mechanotransduction (MET) channel in inner-ear hair cells that binds directly to TMC1 and TMC2 through a conserved hydrophobic groove situated between transmembrane domains 2 and 3, as revealed by co-crystal structure analysis showing structural similarity to KChIP1 binding of Kv4 channels (PMID:34089643). CIB3 can functionally substitute for CIB2 in cochlear hair cells to support mechanoelectrical transduction, and in vestibular hair cells CIB2 and CIB3 act redundantly such that double knockout completely abolishes MET currents and causes severe balance deficits, while single knockouts produce region-specific stereocilia maintenance defects (PMID:34089643, PMID:37001993).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2021 High

    Determining how CIB proteins physically engage the MET channel complex, co-crystallization of CIB3 with the TMC1 CIB-binding domain revealed that CIB3 binds TMC1/2 via a conserved hydrophobic groove between transmembrane domains 2 and 3, structurally analogous to KChIP auxiliary subunit binding of Kv4 channels, establishing CIB3 as a bona fide auxiliary subunit of the MET channel.

    Evidence X-ray co-crystal structure of CIB3–TMC1 CIB-binding domain, binding assays, and functional validation in knockout mice

    PMID:34089643

    Open questions at the time
    • Full-length TMC1/2–CIB3 complex structure not resolved
    • Whether CIB3 modulates channel gating kinetics or solely stabilizes TMC localization is not distinguished
    • Calcium-dependence of CIB3–TMC interaction not fully characterized
  2. 2021 High

    Establishing functional redundancy with CIB2, experiments showed that CIB3 can substitute for CIB2 in supporting cochlear MET currents and that deafness-causing CIB2 mutations disrupt TMC1/2 localization, demonstrating that CIB family members are interchangeable in maintaining hair-cell mechanotransduction.

    Evidence Electrophysiological MET current recordings and immunolocalization in CIB2/CIB3 knockout mouse cochlear hair cells

    PMID:34089643

    Open questions at the time
    • Whether CIB3 loss alone causes any auditory phenotype in vivo is not resolved
    • Quantitative differences in MET current properties between CIB2- and CIB3-supported channels not characterized
  3. 2023 High

    Extending the redundancy model to the vestibular system, double knockout of Cib2 and Cib3 completely abolished MET currents in vestibular hair cells and caused severe balance deficits, while single knockouts revealed region-specific roles—CIB2 in striolar and CIB3 in extrastriolar vestibular hair cells—for stereocilia maintenance.

    Evidence Electrophysiology and fluorescence microscopy of stereocilia in single and double Cib2/Cib3 knockout mice

    PMID:37001993

    Open questions at the time
    • Molecular basis for differential expression of CIB2 versus CIB3 across vestibular regions unknown
    • Whether CIB3 has non-redundant functions in extrastriolar hair cells beyond stereocilia maintenance not tested
  4. 2024 Low

    A preprint reported CIB3 localization at intestinal microvillar tips and its in vitro association with a TMC5 fragment, raising the possibility that CIB3 participates in a mechanosensitive complex outside the inner ear.

    Evidence (preprint) Fluorescence microscopy colocalization and pulldown of TMC5 fragment with CIB3 in intestinal epithelial cells

    PMID:bio_10.1101_2024.08.22.609173

    Open questions at the time
    • Single pulldown with a fragment, no full-length TMC5–CIB3 binding demonstrated
    • No functional knockout validation of CIB3 in intestinal epithelium
    • Mechanosensitive function at microvillar tips not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether CIB3 directly modulates MET channel gating kinetics versus solely stabilizing TMC localization, what determines its region-specific expression pattern in the vestibular system, and whether the intestinal TMC5–CIB3 interaction is physiologically relevant.
  • No reconstituted MET channel system to dissect CIB3 gating effects
  • Transcriptional regulation of CIB3 expression not characterized
  • Full-length TMC5–CIB3 complex formation and in vivo intestinal function unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005929 cilium 3
Pathway
R-HSA-9709957 Sensory Perception 3
Partners
CIB2TMC1TMC2

Evidence

Reading pass · 4 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, binding to TMC1/2 through a domain flanked by transmembrane domains 2 and 3; the co-crystal structure of the CIB-binding domain of TMC1 with CIB3 reveals interactions mediated through a conserved CIB hydrophobic groove, structurally similar to KChIP1 binding of Kv4 channels. X-ray crystallography, co-crystal structure, functional studies in mice (KO), binding assays Neuron High 34089643
2021 CIB3 can functionally substitute for CIB2 in cochlear hair cells to support mechanoelectrical transduction, and CIB2 regulates TMC1/2 localization and function; deafness-causing CIB2 mutations affect these processes. Functional studies in CIB2/CIB3 knockout mice, electrophysiology (MET current recordings), immunolocalization Neuron High 34089643
2023 CIB2 and CIB3 act redundantly to regulate MET currents in vestibular hair cells (VHCs); Cib2/Cib3 double knockout completely abolishes MET currents in VHCs and leads to severe balance deficits, while single knockouts show region-specific stereocilia maintenance defects (CIB2 in striolar, CIB3 in extrastriolar VHCs). Double and single knockout mice, electrophysiology (MET currents), fluorescence microscopy of stereocilia The Journal of neuroscience High 37001993
2024 CIB3 localizes to microvillar tips in intestinal epithelial cells near glycocalyx insertion sites and forms a complex with TMC5 (a fragment of TMC5 binds CIB3 in vitro), suggesting CIB3 participates in a mechanosensitive complex at microvillar tips analogous to its role in inner ear stereocilia. Colocalization (fluorescence microscopy), in vitro complex formation (pulldown of TMC5 fragment with CIB3) bioRxivpreprint Low bio_10.1101_2024.08.22.609173

Source papers

Stage 0 corpus · 11 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 63 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 17 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
2021 Arabidopsis CIB3 regulates photoperiodic flowering in an FKF1-dependent way. Bioscience, biotechnology, and biochemistry 10 33686404
2018 Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly. Molecular biology of the cell 7 29874146