Structure of the human TRPM4 ion channel in a lipid nanodisc

• Published in: Science (American Association for the Advancement of Science) Vol. 359; no. 6372; pp. 228 - 232
• Main Authors: Autzen, Henriette E., Myasnikov, Alexander G., Campbell, Melody G., Asarnow, Daniel, Julius, David, Cheng, Yifan
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.01.2018
• Subjects: Architecture; Binding Sites; Calcium; Calcium (intracellular); Calcium - chemistry; Calcium - metabolism; Calcium channels; Calcium channels (voltage-gated); Calcium-binding protein; Cations; Cryoelectron Microscopy; Disorders; Electric potential; Electron microscopy; Humans; Hydrophobic and Hydrophilic Interactions; Intracellular; Ion channels; Lipids; Menthol; Models, Molecular; Nanostructures; Protein Conformation; Protein Domains; Protein Structure, Secondary; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Recombinant Proteins - ultrastructure; Transient receptor potential proteins; TRPM Cation Channels - chemistry; TRPM Cation Channels - metabolism; TRPM Cation Channels - ultrastructure
• DOI: 10.1126/science.aar4510
• ISSN: 0036-8075; 1095-9203

Transient receptor potential melastatin (TRPM) ion channels constitute the largest TRP subfamily and are involved in many physiological processes. TRPM8 is the primary cold and menthol sensor, and TRPM4 is associated with cardiovascular disorders. Yin et al. and Autzen et al. shed light on the general architecture of the TRPM subfamily by solving the structures of TRPM8 and TRPM4, respectively (see the Perspective by Bae et al. ). The three-layered architecture of the TRPM8 channel provides the framework for understanding the mechanisms of cold and menthol sensing. The two distinct closed states of TRPM4, with and without calcium, reveal a calcium-binding site and calcium-binding-induced conformational changes. Science , this issue p. 237 , p. 228 ; see also p. 160 Structures of a human cation channel revealed by single-particle cryo–electron microscopy elucidate the calcium-binding site. 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.