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Structure of the human TRPM4 ion channel in a lipid nanodisc.

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.

SUBMITTER: Autzen HE

PROVIDER: S-EPMC5898196 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Structure of the human TRPM4 ion channel in a lipid nanodisc.

Autzen Henriette E HE Myasnikov Alexander G AG Campbell Melody G MG Asarnow Daniel D Julius David D Cheng Yifan Y

Science (New York, N.Y.) 20171207 6372

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, ...[more]

PMID: 29217581

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