Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-12-04 DOI:10.1016/j.str.2024.11.005

Peter Rory Hall, Thibault Jouen-Tachoire, Marcus Schewe, Peter Proks, Thomas Baukrowitz, Elisabeth P. Carpenter, Simon Newstead, Karin E.J. Rödström, Stephen J. Tucker

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Abstract

TASK-1 and TASK-3 are pH-sensitive two-pore domain (K2P/KCNK) K⁺ channels. Their functional roles make them promising targets for treatment of multiple disorders including sleep apnea, pain, and atrial fibrillation. Mutations in these channels are also associated with neurodevelopmental and hypertensive disorders. A previous crystal structure of TASK-1 revealed a lower “X-gate” as a hotspot for missense gain-of-function (GoF) mutations associated with DDSA (developmental delay with sleep apnea). However, the mechanisms of gating in TASK channels are still not fully understood. Here, we resolve structures for both human TASK-1 and TASK-3 by cryoelectron microscopy (cryo-EM), as well as a recurrent TASK-3 variant (G236R) associated with KCNK9 imprinting syndrome (KIS) (formerly known as Birk-Barel syndrome). Combined with functional studies of the X-gating mechanism, we provide evidence for how a highly conserved gating mechanism becomes defective in disease, and also provide further insight into the pathway of conformational changes that underlie the pH-dependent inhibition of TASK channel activity.

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任务-1和任务-3 K2P通道的结构提供了对其门控和疾病功能障碍的深入了解

TASK-1和TASK-3是ph敏感的双孔域（K2P/KCNK） K+通道。它们的功能作用使它们成为治疗多种疾病的有希望的靶点，包括睡眠呼吸暂停、疼痛和心房颤动。这些通道的突变也与神经发育和高血压疾病有关。先前的TASK-1晶体结构显示，较低的“x门”是与DDSA（发育迟缓伴睡眠呼吸暂停）相关的错误意义功能获得（GoF）突变的热点。然而，在TASK通道中的门控机制仍然没有被完全理解。在这里，我们通过低温电子显微镜（cro - em）分析了人类TASK-1和TASK-3的结构，以及与KCNK9印迹综合征（KIS）（以前称为Birk-Barel综合征）相关的复发性TASK-3变体（G236R）。结合对x -门控机制的功能研究，我们为高度保守的门控机制如何在疾病中出现缺陷提供了证据，并进一步深入了解了ph依赖性抑制TASK通道活性的构象变化途径。

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

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.