Structure of the human TRPM4 ion channel in a lipid nanodisc

  • Science. 2018 Jan 12;359(6372):228-232. doi: 10.1126/science.aar4510.
Henriette E Autzen  1  2 ,  Alexander G Myasnikov  1 ,  Melody G Campbell  1 ,  Daniel Asarnow  1 ,  David Julius  3 ,  Yifan Cheng  1  4
Affiliations
  • 1. Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
  • 2. Department of Molecular Biology and Genetics, University of Aarhus, 8000 Aarhus, Denmark.
  • 3. Department of Physiology, University of California, San Francisco, CA 94143, USA.
  • 4. Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
PMID: 29217581 DOI: 10.1126/science.aar4510
Abstract

Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many Other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.