Aromatic interactions with membrane modulate human BK channel activation
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
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.
Reviewing Editor
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Version history
- Received: February 5, 2020
- Accepted: June 28, 2020
- Accepted Manuscript published: June 29, 2020 (version 1)
- Version of Record published: July 20, 2020 (version 2)
- Version of Record updated: February 17, 2021 (version 3)
Copyright
© 2020, Yazdani et al.
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.
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