Journal Article

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

She, Ji, Bai, Xiao-chen, Jiang, Youxing, Guo, Jiangtao, Zeng, Weizhong, Chen, Qingfeng

2017

Overview

TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ) -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 Ca 2+ - and PtdIns(4,5)P 2 -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. Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective cation channel, in the apo and ATP-bound states. Scoping out TRPM channels Melastatin-related transient receptor potential (TRPM) ion channels are the largest group of the TRP superfamily and, as such, are widespread throughout the body with diverse physiological roles including heat and taste sensation and regulating ion homeostasis. For example, TRPM4 is a Ca 2+ -activated non-selective channel expressed in many of the central organs including the brain and heart, and is involved in the cardiac rhythm, breath pacemaking and insulin secretion. In this issue of Nature , two groups report the structure of TRPM4 by electron cryo-microscopy. Wei Lü and colleagues solved the structure of human TRPM4, which shows an umbrella-like structure, bound to Ca(ɪɪ) and decavanadate. Youxing Jiang and colleagues report the structure of mouse TRPM4 with and without ATP, which inhibits channel activity. These studies provide the first structural insights into the TRPM family.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/535/1258/1259 / 631/57/2270/1140 / 82/83 / Adenosine triphosphate / Adenosine Triphosphate - chemistry / Adenosine Triphosphate - metabolism / Adenosine Triphosphate - pharmacology / Animals / ATP / Binding Sites / Calcium / Calcium - metabolism / Cations / Cells / Channel gating / Cryoelectron Microscopy / Enzymes / Humanities and Social Sciences / Ion channels / Ligands / Lipids / Membranes / Mice / Microscopy / Models, Molecular / Molecular structure / multidisciplinary / Phosphatidylinositol 4,5-diphosphate / Protein Domains / Protein Structure, Secondary / Proteins / Science / Structure / Substrate Specificity / Transient receptor potential proteins / TRPM Cation Channels - antagonists & inhibitors / TRPM Cation Channels - chemistry / TRPM Cation Channels - metabolism / TRPM Cation Channels - ultrastructure