MyoD-family inhibitor proteins act as auxiliary subunits of Piezo channels

  • Science. 2023 Aug 18;381(6659):799-804. doi: 10.1126/science.adh8190.
Zijing Zhou  #  1  2 ,  Xiaonuo Ma  #  3  4 ,  Yiechang Lin  5 ,  Delfine Cheng  1  2 ,  Navid Bavi  6 ,  Genevieve A Secker  7 ,  Jinyuan Vero Li  1  2 ,  Vaibhao Janbandhu  1  2 ,  Drew L Sutton  7  8 ,  Hamish S Scott  7  8  9 ,  Mingxi Yao  10 ,  Richard P Harvey  1  2  11 ,  Natasha L Harvey  7  8 ,  Ben Corry  5 ,  Yixiao Zhang  3  4 ,  Charles D Cox  1  12
Affiliations
  • 1. Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
  • 2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
  • 3. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 5. Research School of Biology, Australian National University, Acton, ACT 2601, Australia.
  • 6. Department of Biochemistry and Molecular Biophysics, University of Chicago, Chicago, IL 60637, USA.
  • 7. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia.
  • 8. Adelaide Medical School, University of Adelaide, Adelaide, SA 5005 Australia.
  • 9. Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA 5000, Australia.
  • 10. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, China.
  • 11. School of Biotechnology and Biomolecular Science, University of New South Wales Sydney, Kensington, NSW 2052, Australia.
  • 12. School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales Sydney, Kensington, NSW 2052, Australia.
  • # Contributed equally.
PMID: 37590348 DOI: 10.1126/science.adh8190
Abstract

Piezo channels are critical cellular sensors of mechanical forces. Despite their large size, ubiquitous expression, and irreplaceable roles in an ever-growing list of physiological processes, few Piezo channel-binding proteins have emerged. In this work, we found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryogenic electron microscopy, we mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease.