美国Van Andel研究所Wei Lü、Juan Du等研究人员合作解析了人类钙稳态调节蛋白2（CALHM2）的结构和门控机制。2019年11月27日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员报道了人类CALHM2通道在无Ca²⁺活性或开放状态以及钌红（RUR）结合抑制状态下的冷冻电子显微镜结构，其分辨率高达2.7埃。研究结果表明，纯化的CALHM2通道既形成间隙连接又形成半通道。前体显示跨膜结构域（螺旋S1-S4）相对于具有类似拓扑结构的其他通道的镜像排列，例如连接蛋白、内毒素和体积调节的阴离子通道。与RUR结合后，研究人员观察到收缩的孔具有明显的孔衬螺旋S1构象变化，该结构从垂直位置向抬升位置向孔轴摆动近60°。研究人员提出了一种两段式浇口机制，其中S1螺旋粗调，N末端螺旋微调孔径。研究人员在螺旋S1附近鉴定了一个RUR结合位点，该位点可能使该螺旋稳定在提升的构象中，从而引起通道抑制。这些工作详细阐述了CALHM2通道架构和对称性的原理，以及构成通道抑制的基础。

据了解，钙稳态调节因子（CALHM）是电压门控、Ca²⁺抑制的非选择性离子通道，可作为主要的ATP释放通道，并且在味觉信号传导和神经元毒性中起重要作用。CALHM的功能障碍以前与神经系统疾病有关。

附：英文原文

Title: The structures and gating mechanism of human calcium homeostasis modulator 2

Author: Wooyoung Choi, Nicolina Clemente, Weinan Sun, Juan Du, Wei L

Issue&Volume: 2019-11-27

Abstract: Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca2+-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal toxicity13. Dysfunction of CALHMs has previously been linked to neurological disorders1. Here we present cryo-electron microscopy structures of the human CALHM2 channel in the Ca2+-free active or open state and in the ruthenium red (RUR)-bound inhibited state, at resolutions up to 2.7 . Our work shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the transmembrane domains (helices S1S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels48. Upon binding to RUR, we observed a contracted pore with notable conformational changes of the pore-lining helix S1, which swings nearly 60 towards the pore axis from a vertical to a lifted position. We propose a two-section gating mechanism in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size. We identified a RUR-binding site near helix S1 that may stabilize this helix in the lifted conformation, giving rise to channel inhibition. Our work elaborates on the principles of CALHM2 channel architecture and symmetry, and the mechanism that underlies channel inhibition. Cryo-electron microscopy structures of the active and inhibited human CALHM2 channel suggest a two-stage gating mechanism in which the S1 helix adjusts the pore size, which is then fine-tuned by the N-terminal helix.

DOI: 10.1038/s41586-019-1781-3

Source:https://www.nature.com/articles/s41586-019-1781-3