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二聚体机械敏感 OSCA/TMEM63 通道的激活机制。

Activation mechanisms of dimeric mechanosensitive OSCA/TMEM63 channels.

机构信息

Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, 310000, China.

Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China.

出版信息

Nat Commun. 2024 Aug 29;15(1):7504. doi: 10.1038/s41467-024-51800-0.

Abstract

OSCA/TMEM63 channels, which have transporter-like architectures, are bona fide mechanosensitive (MS) ion channels that sense high-threshold mechanical forces in eukaryotic cells. The activation mechanism of these transporter-like channels is not fully understood. Here we report cryo-EM structures of a dimeric OSCA/TMEM63 pore mutant OSCA1.1-F516A with a sequentially extracellular dilated pore in a detergent environment. These structures suggest that the extracellular pore sequential dilation resembles a flower blooming and couples to a sequential contraction of each monomer subunit towards the dimer interface and subsequent extrusion of the dimer interface lipids. Interestingly, while OSCA1.1-F516A remains non-conducting in the native lipid environment, it can be directly activated by lyso-phosphatidylcholine (Lyso-PC) with reduced single-channel conductance. Structural analysis of OSCA1.1-F516A in lyso-PC-free and lyso-PC-containing lipid nanodiscs indicates that lyso-PC induces intracellular pore dilation by attracting the M6b to upward movement away from the intracellular side thus extending the intracellular pore. Further functional studies indicate that full activation of MS OSCA/TMEM63 dimeric channels by high-threshold mechanical force also involves the opening of both intercellular and extracellular pores. Our results provide the fundamental activation paradigm of the unique transporter-like MS OSCA/TMEM63 channels, which is likely applicable to functional branches of the TMEM63/TMEM16/TMC superfamilies.

摘要

OSCA/TMEM63 通道具有转运蛋白样结构,是真正的机械敏感(MS)离子通道,可感知真核细胞中的高阈值机械力。这些转运蛋白样通道的激活机制尚未完全了解。在这里,我们报告了在去污剂环境中具有顺序细胞外扩张孔的二聚体 OSCA/TMEM63 孔突变体 OSCA1.1-F516A 的冷冻电镜结构。这些结构表明,细胞外孔的顺序扩张类似于花朵的绽放,并与每个单体亚基向二聚体界面的顺序收缩以及随后二聚体界面脂质的挤出相偶联。有趣的是,虽然 OSCA1.1-F516A 在天然脂质环境中仍然不导电,但它可以被溶血磷脂酰胆碱(Lyso-PC)直接激活,同时单通道电导降低。在无 Lyso-PC 和含有 Lyso-PC 的脂质纳米盘中对 OSCA1.1-F516A 的结构分析表明,Lyso-PC 通过吸引 M6b 向上移动远离细胞内侧面,从而扩展细胞内孔,从而诱导细胞内孔扩张。进一步的功能研究表明,高阈值机械力对 MS OSCA/TMEM63 二聚体通道的完全激活还涉及细胞间和细胞外孔的打开。我们的结果提供了独特的转运蛋白样 MS OSCA/TMEM63 通道的基本激活范例,该范例可能适用于 TMEM63/TMEM16/TMC 超家族的功能分支。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8483/11362595/4d56af93424a/41467_2024_51800_Fig1_HTML.jpg

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