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

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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.

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All data generated or analysed during this study are included in the manuscript and supporting file.

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Go Kasuya

Department of Physiology, Jichi Medical Univesity, Shimotsuke, Japan

For correspondence
gokasuya@jichi.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1756-5764
Koichi Nakajo

Department of Physiology, Jichi Medical Univesity, Shimotsuke, Japan

For correspondence
knakajo@jichi.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0766-7281

Funding

Japan Society for the Promotion of Science (19K23833)

Go Kasuya

Japan Society for the Promotion of Science (20H03200)

Go Kasuya

Japan Society for the Promotion of Science (17K08552)

Koichi Nakajo

Japan Society for the Promotion of Science (21K06786)

Koichi Nakajo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were approved by the Animal Care Committee of Jichi Medical University(Japan) under protocol no. 18027-03 and were performed according to guidelines.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.