小柯机器人

美国范安德研究所Wei Lü等研究人员合作发现，生理温度驱动TRPM4配体识别和门控。相关论文于2024年5月15日在线发表于国际学术期刊《自然》。

研究人员展示了对温度敏感的Ca²⁺激活离子通道TRPM4的结构和功能随温度发生的变化。通过使用单颗粒冷冻电镜研究生理温度下制备的TRPM4，研究人员发现了一种“温暖”构象，它不同于在较低温度下观察到的构象。这种构象由胞内结构域中一个随温度变化的Ca²⁺结合位点驱动，对于TRPM4在生理环境下的功能至关重要。研究人员证明，配体（例如十钒酸盐/一种正向调节因子）和ATP/一种抑制剂）在生理温度下与TRPM4不同位置的结合比在较低温度下要好，而且这些位点具有真正的功能相关性。

研究人员通过捕捉TRPM4在生理温度下不同功能状态的结构快照，阐明了TRPM4的门控机制，并揭示了在较低温度下观察不到的通道开放。该研究提供了一个离子通道的配体识别和调控随温度变化的例子，并强调了在生理温度下研究大分子的重要性。它还为破译热敏感TRPM通道如何感知温度变化提供了一个潜在的分子框架。

研究人员表示，温度对大分子功能影响深远，尤其是对具有温度敏感性的蛋白质。然而，通常在非生理温度下进行的生物物理研究往往忽视了温度的影响，从而可能导致不准确的机理和药理认识。

附：英文原文

Title: Physiological temperature drives TRPM4 ligand recognition and gating

Author: Hu, Jinhong, Park, Sung Jin, Walter, Tyler, Orozco, Ian J., ODea, Garrett, Ye, Xinyu, Du, Juan, L, Wei

Issue&Volume: 2024-05-15

Abstract: Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity1,2. However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca2+-activated ion channel3,4,5,6,7. By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a ‘warm’ conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca2+-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator)8 and ATP (an inhibitor)9, bind to different locations of TRPM4 at physiological temperatures than at lower temperatures10,11, and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes.

DOI: 10.1038/s41586-024-07436-7

Source: https://www.nature.com/articles/s41586-024-07436-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html