Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-04-29 DOI:10.1073/pnas.2421900122

Andrei Y. Kostritskii, Yulia Kostritskaia, Natalia Dmitrieva, Tobias Stauber, Jan-Philipp Machtens

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Abstract

TMEM16A is a Ca 2+ -activated Cl − channel that has crucial roles in various physiological and pathological processes. However, the structure of the open state of the channel and the mechanism of Ca 2+ -induced pore opening have remained elusive. Using extensive molecular dynamics simulations, protein structure prediction, and patch-clamp electrophysiology, we demonstrate that TMEM16A opens a hydrated Cl − -conductive pore via a pi-helical transition in transmembrane segment 4 (TM4). We also describe a coupling mechanism that links pi-helical transition and pore opening to the Ca 2+ -induced conformational changes in TMEM16A. Furthermore, we designed a pi-helix-stabilizing mutation (I551P) that facilitates TMEM16A activation, revealing atomistic details of the ion-conduction mechanism. Finally, AlphaFold2 structure predictions revealed the importance of the pi helix in TM4 to structure–function relations in TMEM16 and the related OSCA/TMEM63 family, further highlighting the relevance of dynamic pi helices for gating in various ion channels.

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钙激活的氯离子通道TMEM16A通过跨膜段4的pi-螺旋过渡打开

TMEM16A是ca2 +激活的Cl -通道，在各种生理和病理过程中起重要作用。然而，通道开放状态的结构和ca2 +诱导开孔的机制仍然是未知的。通过广泛的分子动力学模拟、蛋白质结构预测和膜片钳电生理学，我们证明了TMEM16A通过跨膜段4 （TM4）的pi-螺旋转变打开了一个水合Cl−导电孔。我们还描述了一种耦合机制，该机制将pi螺旋转变和孔隙打开与ca2 +诱导的TMEM16A构象变化联系起来。此外，我们设计了一个pi-螺旋稳定突变（I551P），促进了TMEM16A的激活，揭示了离子传导机制的原子细节。最后，AlphaFold2结构预测揭示了TM4中pi螺旋对TMEM16和相关的OSCA/TMEM63家族结构-功能关系的重要性，进一步强调了动态pi螺旋对各种离子通道门通的相关性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.