Architecture of the TRPM subfamily 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.

中文翻译：

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脂质纳米盘中人TRPM4离子通道的结构

TRPM 亚家族的结构瞬时受体电位褪黑素 (TRPM) 离子通道构成最大的 TRP 亚家族并参与许多生理过程。TRPM8 是主要的寒冷和薄荷醇传感器，TRPM4 与心血管疾病有关。殷等人。和 Autzen 等人。通过分别求解 TRPM8 和 TRPM4 的结构，阐明了 TRPM 亚家族的一般架构（参见 Bae 等人的观点）。TRPM8 通道的三层架构为理解冷感和薄荷醇感测机制提供了框架。TRPM4 的两种不同的闭合状态，有和没有钙，揭示了钙结合位点和钙结合诱导的构象变化。科学，这个问题 p。237 页。228; 另见第。160 单粒子低温电子显微镜揭示的人类阳离子通道结构阐明了钙结合位点。瞬时受体电位 (TRP) 褪黑素 4 (TRPM4) 是一种广泛表达的阳离子通道，与多种心血管疾病相关。TRPM4 由增加的细胞内钙离子以电压依赖性方式激活，但与许多其他 TRP 通道不同，它仅可渗透单价阳离子。在这里，我们展示了两种全长人类 TRPM4 结构，嵌入脂质纳米圆盘中，分辨率约为 3 埃，由单粒子低温电子显微镜确定。这些有和没有钙结合的结构揭示了这个主要 TRP 通道亚家族的一般结构，以及 S1-S4 结构域细胞内侧明确定义的钙结合位点。这些结构对应于两个不同的闭合状态。钙结合诱导构象变化，可能为电压依赖性打开通道做好准备。