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Nature. 2017 Dec 14;552(7684):205-209. doi: 10.1038/nature24997. Epub 2017 Dec 6.

Structures of the calcium-activated, non-selective cation channel TRPM4.

Guo J1,2, She J1,2, Zeng W1,2,3, Chen Q1,2,3, Bai XC2,4, Jiang Y1,2,3.

Author information

1
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
2
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816, USA.
3
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
4
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.

Abstract

TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.

PMID:
29211714
PMCID:
PMC5901961
DOI:
10.1038/nature24997
[Indexed for MEDLINE]
Free PMC Article

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