1. Structural Biology and Molecular Biophysics
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Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating

  1. Marina A Kasimova
  2. Debanjan Tewari
  3. John B Cowgill
  4. Willy Carrasquel Ursuleaz
  5. Jenna L Lin
  6. Lucie Delemotte  Is a corresponding author
  7. Baron Chanda  Is a corresponding author
  1. KTH Royal Institute of Technology, Sweden
  2. University of Wisconsin-Madison, United States
Research Article
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Cite this article as: eLife 2019;8:e53400 doi: 10.7554/eLife.53400

Abstract

In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltage-sensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (~20 ms) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.

Data availability

Simulations were carried out at the Pittsburg Supercomputing center which is funded by NIGMS. Data is available at: https://psc.edu/anton-project-summaries

Article and author information

Author details

  1. Marina A Kasimova

    Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7497-9448
  2. Debanjan Tewari

    Department of Neuroscience, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  3. John B Cowgill

    Department of Neuroscience, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7968-8359
  4. Willy Carrasquel Ursuleaz

    Department of Neuroscience, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  5. Jenna L Lin

    Department of Neuroscience, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  6. Lucie Delemotte

    Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden
    For correspondence
    lucie.delemotte@scilifelab.se
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0828-3899
  7. Baron Chanda

    Department of Neuroscience, University of Wisconsin-Madison, Madison, United States
    For correspondence
    chanda@wisc.edu
    Competing interests
    Baron Chanda, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4954-7034

Funding

National Institute of Neurological Disorders and Stroke (NS101723)

  • Baron Chanda

National Heart, Lung, and Blood Institute (HL-07936-18)

  • John B Cowgill

National Institute of General Medical Sciences (GM008293)

  • Jenna L Lin

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

Reviewing Editor

  1. Richard W Aldrich, The University of Texas at Austin, United States

Publication history

  1. Received: November 7, 2019
  2. Accepted: November 19, 2019
  3. Accepted Manuscript published: November 27, 2019 (version 1)
  4. Version of Record published: December 10, 2019 (version 2)

Copyright

© 2019, Kasimova 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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