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PreprintCited by 8Hearing, Cochlea, Tinnitus, GeneticsIon Channels and ReceptorsIon channel regulation and function

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Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels

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Giese, Arnaud P. J., Weng, Wei-Hsiang, Kindt, Katie S., Chang, Hui Ho Vanessa, Montgomery, Jonathan S., Ratzan, Evan M., Beirl, Alisha J., Rivera, Roberto Aponte, Lotthammer, Jeffrey M., Walujkar, Sanket, Foster, Mark P., Zobeiri, Omid A., Holt, Jeffrey R., Riazuddin, Saima, Cullen, Kathleen E., Sotomayor, Marcos, Ahmed, Zubair M.·2023·eLife
DOI 10.1101/2023.05.26.542533PMC PMC10312449

Preprint — published as 10.7554/elife.89719.3 · Paper page

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Abstract

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line. Our AlphaFold 2 models suggest that vertebrate CIB proteins can simultaneously interact with at least two cytoplasmic domains of TMC1 and TMC2 as validated using nuclear magnetic resonance spectroscopy of TMC1 fragments interacting with CIB2 and CIB3. Molecular dynamics simulations of TMC1/2 complexes with CIB2/3 predict that TMCs are structurally stabilized by CIB proteins to form cation channels. Overall, our work demonstrates that intact CIB2/3 and TMC1/2 complexes are integral to hair-cell MET function in vertebrate mechanosensory epithelia.

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Metadata

Authors
Giese, A. P. J., Weng, W.-H., Kindt, K. S., Chang, H. H. V., Montgomery, J. S., Ratzan, E. M., Beirl, A. J., Rivera, R. A., Lotthammer, J. M., Walujkar, S., Foster, M. P., Zobeiri, O. A., Holt, J. R., Riazuddin, S., Cullen, K. E., Sotomayor, M., & Ahmed, Z. M.
Affiliations
  • University of Maryland, Baltimore (US)
  • The Ohio State University (US)
  • National Institutes of Health (US)
  • McGill University (CA)
  • Boston Children's Hospital (US)
  • Johns Hopkins University (US)
Corresponding author
  • Sotomayor, Marcos
  • Ahmed, Zubair M.
ORCID
Venue
eLife
Publisher
openRxiv
Published
2023-05-30
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2023.05.26.542533
PMC
PMC10312449
OpenAlex
W4378837212
Cited by
8
References
2
Citations by year
2025: 3 · 2024: 3 · 2023: 2
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Ohio State University
  • Ohio Supercomputer Center (PAS1037, PAA0217)
  • National Institutes of Health (1ziadc000085-01, 1uf1ns111695-01)
  • National Institute on Deafness and Other Communication Disorders (1ZIADC000085-01, R01DC018304, R01DC015271, R01DC012564, R01DC018061, R01DC002390)
  • National Institute of General Medical Sciences (T32GM144293)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
TMC-1, TMC2, CIB2, mechanoelectrical transduction, hair cell mechanotransduction, cation channels, heteromeric protein complexes, cochlea, vestibular organs, lateral line, zebrafish, mice, protein-protein interaction

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