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S1 片段与 KCNE3 之间的优化紧密结合对于 KCNQ1-KCNE3 通道复合物的组成型开放性质是必需的。

Optimized tight binding between the S1 segment and KCNE3 is required for the constitutively open nature of the KCNQ1-KCNE3 channel complex.

机构信息

Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Japan.

出版信息

Elife. 2022 Nov 4;11:e81683. doi: 10.7554/eLife.81683.

DOI:10.7554/eLife.81683
PMID:36331187
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9671499/
Abstract

Tetrameric voltage-gated K channels have four identical voltage sensor domains, and they regulate channel gating. KCNQ1 (Kv7.1) is a voltage-gated K channel, and its auxiliary subunit KCNE proteins dramatically regulate its gating. For example, KCNE3 makes KCNQ1 a constitutively open channel at physiological voltages by affecting the voltage sensor movement. However, how KCNE proteins regulate the voltage sensor domain is largely unknown. In this study, by utilizing the KCNQ1-KCNE3-calmodulin complex structure, we thoroughly surveyed amino acid residues on KCNE3 and the S1 segment of the KCNQ1 voltage sensor facing each other. By changing the side-chain bulkiness of these interacting amino acid residues (volume scanning), we found that the distance between the S1 segment and KCNE3 is elaborately optimized to achieve the constitutive activity. In addition, we identified two pairs of KCNQ1 and KCNE3 mutants that partially restored constitutive activity by co-expression. Our work suggests that tight binding of the S1 segment and KCNE3 is crucial for controlling the voltage sensor domains.

摘要

四聚体电压门控钾通道具有四个相同的电压传感器结构域，它们调节通道门控。KCNQ1（Kv7.1）是一种电压门控钾通道，其辅助亚基 KCNE 蛋白极大地调节其门控。例如，KCNE3 通过影响电压传感器的运动，使 KCNQ1 在生理电压下成为一种组成型开放通道。然而，KCNE 蛋白如何调节电压传感器结构域在很大程度上尚不清楚。在这项研究中，我们利用 KCNQ1-KCNE3-钙调蛋白复合物结构，全面研究了 KCNE3 上和 KCNQ1 电压传感器 S1 段相互面对的氨基酸残基。通过改变这些相互作用的氨基酸残基的侧链体积（体积扫描），我们发现 S1 段和 KCNE3 之间的距离被精心优化以实现组成型活性。此外，我们鉴定了两对 KCNQ1 和 KCNE3 突变体，它们通过共表达部分恢复了组成型活性。我们的工作表明，S1 段和 KCNE3 的紧密结合对于控制电压传感器结构域至关重要。

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