Structures of the TMC-1 complex illuminate mechanosensory transduction

Jeong, Hanbin; Clark, Sarah; Goehring, April; Dehghani-Ghahnaviyeh, Sepehr; Rasouli, Ali; Tajkhorshid, Emad; Gouaux, Eric

doi:10.1038/s41586-022-05314-8

Structures of the TMC-1 complex illuminate mechanosensory transduction

Journal Article · Wed Oct 12 00:00:00 EDT 2022 · Nature (London)

DOI:https://doi.org/10.1038/s41586-022-05314-8· OSTI ID:2424196

Jeong, Hanbin ^[1]; Clark, Sarah ^[1]; Goehring, April ^[1]; ^[2]; Rasouli, Ali ^[2]; ^[2]; ^[1]

Oregon Health and Science University, Portland, OR (United States)
University of Illinois at Urbana-Champaign, IL (United States)

The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel1. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation Supercomputing Centers; Pittsburgh Supercomputing Center; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2424196

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7933 Vol. 610; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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