Aromatic interactions with membrane modulate human BK channel activation

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Abstract

Large-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca²⁺. The only covalent connection between the cytosolic Ca²⁺ sensing domain and the TM pore and voltage sensing domains is a 15-residue 'C-linker'. To determine the linker’s role in human BK activation, we designed a series of linker sequence scrambling mutants to suppress potential complex interplay of specific interactions with the rest of the protein. The results revealed a surprising sensitivity of BK activation to the linker sequence. Combining atomistic simulations and further mutagenesis experiments, we demonstrated that nonspecific interactions of the linker with membrane alone could directly modulate BK activation. The C-linker thus plays more direct roles in mediating allosteric coupling between BK domains than previously assumed. Our results suggest that covalent linkers could directly modulate TM protein function and should be considered an integral component of the sensing apparatus.

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

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Mahdieh Yazdani

Chemistry, University of Massachusetts, Amherst, Amherst, United States

Competing interests
The authors declare that no competing interests exist.
Guohui Zhang

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

Competing interests
The authors declare that no competing interests exist.
Zhiguang Jia

Chemistry, University of Massachusetts, Amherst, Amherst, United States

Competing interests
The authors declare that no competing interests exist.
Jingyi Shi

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

Competing interests
The authors declare that no competing interests exist.
Jianmin Cui

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

For correspondence
jcui@wustl.edu

Competing interests
The authors declare that no competing interests exist.
Jianhan Chen

Chemistry; Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, United States

For correspondence
jianhanc@umass.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5281-1150

Funding

National Institute of General Medical Sciences (GM114300)

Jianhan Chen

National Heart, Lung, and Blood Institute (HL70393)

Jianhan Chen

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

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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.