Aromatic interactions with membrane modulate human BK channel activation

  1. Mahdieh Yazdani
  2. Guohui Zhang
  3. Zhiguang Jia
  4. Jingyi Shi
  5. Jianmin Cui  Is a corresponding author
  6. Jianhan Chen  Is a corresponding author
  1. University of Massachusetts, Amherst, United States
  2. Washington University in St Louis, United States

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

  1. Mahdieh Yazdani

    Chemistry, University of Massachusetts, Amherst, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. 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.
  3. Zhiguang Jia

    Chemistry, University of Massachusetts, Amherst, Amherst, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. 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.
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Version history

  1. Received: February 5, 2020
  2. Accepted: June 28, 2020
  3. Accepted Manuscript published: June 29, 2020 (version 1)
  4. Version of Record published: July 20, 2020 (version 2)
  5. 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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  1. Mahdieh Yazdani
  2. Guohui Zhang
  3. Zhiguang Jia
  4. Jingyi Shi
  5. Jianmin Cui
  6. Jianhan Chen
(2020)
Aromatic interactions with membrane modulate human BK channel activation
eLife 9:e55571.
https://doi.org/10.7554/eLife.55571

Share this article

https://doi.org/10.7554/eLife.55571

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