TY - JOUR
T1 - Structures of the TMC-1 complex illuminate mechanosensory transduction
AU - Jeong, Hanbin
AU - Clark, Sarah
AU - Goehring, April
AU - Dehghani-Ghahnaviyeh, Sepehr
AU - Rasouli, Ali
AU - Tajkhorshid, Emad
AU - Gouaux, Eric
N1 - We thank T. Nicolson, P. Barr-Gillespie, D. Farrens, M. Mayer, A. Aballay, J. Ge, J. Elferich and members of the Gouaux and Baconguis laboratories for helpful discussions; S. Petrie and B. Jenkins for help with worm spectral imaging; T. Provitola for assistance with figures; A. Reddy for mass spectrometric analysis; J. Meyers and S. Yang for help with cryo-EM screening and data collection; A. Chinn for help with worm growth; and R. Hallford for proof reading. Initial cryo-EM grids were screened at the Pacific Northwest Cryo-EM Center (PNCC), which is supported by NIH grant U24GM129547 and performed at the PNCC at OHSU, accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. The large single-particle cryo-EM dataset was collected at the Janelia Research Campus of the Howard Hughes Medical Institute (HHMI). The OHSU Proteomics Shared Resource is partially supported by NIH core grants P30EY010572 and P30CA069533. This work was supported by NIH grant 1F32DC017894 to S.C. The simulations were supported by the NIH grants, P41-GM104601 and R01-GM123455 to E.T. Simulations were performed using allocations on Anton at Pittsburgh Supercomputing Center (award MCB100017P to E.T.), and XSEDE resources provided by the National Science Foundation Supercomputing Centers (XSEDE grant number MCA06N060 to E.T.). E.G. gratefully acknowledges J. LaCroute and B. LaCroute for support, and is an investigator of the HHMI.
We thank T. Nicolson, P. Barr-Gillespie, D. Farrens, M. Mayer, A. Aballay, J. Ge, J. Elferich and members of the Gouaux and Baconguis laboratories for helpful discussions; S. Petrie and B. Jenkins for help with worm spectral imaging; T. Provitola for assistance with figures; A. Reddy for mass spectrometric analysis; J. Meyers and S. Yang for help with cryo-EM screening and data collection; A. Chinn for help with worm growth; and R. Hallford for proof reading. Initial cryo-EM grids were screened at the Pacific Northwest Cryo-EM Center (PNCC), which is supported by NIH grant U24GM129547 and performed at the PNCC at OHSU, accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. The large single-particle cryo-EM dataset was collected at the Janelia Research Campus of the Howard Hughes Medical Institute (HHMI). The OHSU Proteomics Shared Resource is partially supported by NIH core grants P30EY010572 and P30CA069533. This work was supported by NIH grant 1F32DC017894 to S.C. The simulations were supported by the NIH grants, P41-GM104601 and R01-GM123455 to E.T. Simulations were performed using allocations on Anton at Pittsburgh Supercomputing Center (award MCB100017P to E.T.), and XSEDE resources provided by the National Science Foundation Supercomputing Centers (XSEDE grant number MCA06N060 to E.T.). E.G. gratefully acknowledges J. LaCroute and B. LaCroute for support, and is an investigator of the HHMI.
PY - 2022/10/27
Y1 - 2022/10/27
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-022-05314-8
DO - 10.1038/s41586-022-05314-8
M3 - Article
C2 - 36224384
AN - SCOPUS:85139627942
SN - 0028-0836
VL - 610
SP - 796
EP - 803
JO - Nature
JF - Nature
IS - 7933
ER -