Structural dynamics at cytosolic interprotomer interfaces control gating of a mammalian TRPM5 channel

• 成果类型: Article
• 署名作者: Karuppan, Sebastian; Schrag, Lynn Goss; Pastrano, Caroline M.; Jara-Oseguera, Andres; Zubcevic, Lejla
• 署名单位: University of Kansas; University of Kansas Medical Center; University of Texas System; University of Texas Austin; Arizona State University; Arizona State University-Tempe
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11360
• DOI: 10.1073/pnas.2403333121
• 发表日期: 2024-07-02
• 关键词: ion-channel; receptor; contributes; activation; calcium; locus

摘要

The transient receptor potential melastatin (TRPM) tetrameric cation channels are involved in a wide range of biological functions, from temperature sensing and taste transduction to regulation of cardiac function, inflammatory pain, and insulin secretion. The structurally conserved TRPM cytoplasmic domains make up >70 % of the total protein. To investigate the mechanism by which the TRPM cytoplasmic domains contribute to gating, we employed electrophysiology and cryo-EM to study TRPM5-a channel that primarily relies on activation via intracellular Ca2+. Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca2+- dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca2+ binding, whereby formation and dissolution of cytoplasmic interprotomer interfaces appear to control activation and desensitization of the channel. This study shows the importance of the cytoplasmic assembly in TRPM5 channel function and sets the stage for future investigations of other members of the TRPM family.