Oral Presentation 50th Lorne Proteins Conference 2025

Mechanical activation of OSCA channels opens a lipid lined pore (115030)

Yaoyao Han 1 2 , Zijing Zhou 3 4 , Ruitao Jin 5 , Ben Corry 5 , Charles Cox 3 6 , Yixiao Zhang 1 2 7
  1. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, China
  2. Shanghai Key Laboratory of Aging Studies, Shanghai, China
  3. Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
  4. School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia
  5. Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
  6. School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia
  7. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China

OSCAs and their mammalian orthologs TMEM63s form the largest family of mechanically gated ion channels in plants and animals. Since their recent identification as mechanically gated ion channels, much effort has been given to reveal their molecular structure, including capturing open states of the channel. However, due to difficulty of introducing mechanical force during sample preparation for structural studies, this remains challenging experimentally.  In our recent study1, we used cryo-EM to solve the fully open OSCA1.2 channel in liposomes whose pore is dilated significantly with a large lateral opening to the membrane at the location of the posited pore. Using MD simulations, we identified that lipid headgroups form part of the pore wall, creating a channel wide enough to conducting fully hydrated ions. Electrophysiology data further showed that the lipid headgroups are responsible for the cation selectivity of the channel. We further identified an ‘interlocking’ lipid in OSCA3.1 structures responsible for the higher gating thresholds of this variant, with functional data revealing an increased open probability of the channel in mutants that reduce lipid binding at this position. Together using structural, functional and computational approaches, we demonstrated the functional gating cycle of OSCA/TMEM63 ion channel family and provide the first unequivocal demonstration of proteo-lipid pore. This finding has important mechanistic implications for the TMEM16 and TMC protein families sharing similar topological structures within lipid membrane.

  1. Han, Y., Zhou, Z., Jin, R., Dai, F., Ge, Y., Ju, X., ... & Zhang, Y. (2024). Mechanical activation opens a lipid-lined pore in OSCA ion channels. Nature, 628(8009), 910-918.