Complexes of Vertebrate TMC1/2 and CIB2/3 Proteins Form Hair-cell Mechanotransduction Cation Channels

Overview

Journal bioRxiv

Date 2023 Jul 3

PMID 37398045

Authors

Arnaud P J Giese

Wei-Hsiang Weng

Katie S Kindt

Hui Ho Vanessa Chang

Jonathan S Montgomery

Evan M Ratzan

Alisha J Beirl

Roberto Aponte Rivera

Jeffrey M Lotthammer

Sanket Walujkar

Mark P Foster

Omid A Zobeiri

Jeffrey R Holt

Saima Riazuddin

Kathleen E Cullen

Marcos Sotomayor

Zubair M Ahmed

Affiliations

Soon will be listed here.

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.

Citing Articles

Differential expression of mechanotransduction complex genes in auditory/vestibular hair cells in zebrafish.

Smith E, Sun P, Yu S, Raible D, Nicolson T Front Mol Neurosci. 2023; 16:1274822.

PMID: 38035267 PMC: 10682102. DOI: 10.3389/fnmol.2023.1274822.

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