Structure of the human TRPM4 ion channel in a lipid nanodisc

Science. 2018 Jan 12;359(6372):228-232. doi: 10.1126/science.aar4510. Epub 2017 Dec 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium / chemistry
  • Calcium / metabolism
  • Cryoelectron Microscopy
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipids
  • Models, Molecular
  • Nanostructures
  • Protein Conformation
  • Protein Domains
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • TRPM Cation Channels / chemistry*
  • TRPM Cation Channels / metabolism
  • TRPM Cation Channels / ultrastructure

Substances

  • Lipids
  • Recombinant Proteins
  • TRPM Cation Channels
  • TRPM4 protein, human
  • Calcium