1. Structural Biology and Molecular Biophysics

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
https://doi.org/10.7554/eLife.53400
Share this article
Cite this article
  1. Marina A Kasimova
  2. Debanjan Tewari
  3. John B Cowgill
  4. Willy Carrasquel Ursuleaz
  5. Jenna L Lin
  6. Lucie Delemotte
  7. Baron Chanda
(2019)
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating
eLife 8:e53400.
https://doi.org/10.7554/eLife.53400
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 3,546
    views
  • 521
    downloads
  • 57
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Marina A Kasimova
  2. Debanjan Tewari
  3. John B Cowgill
  4. Willy Carrasquel Ursuleaz
  5. Jenna L Lin
  6. Lucie Delemotte
  7. Baron Chanda
(2019)
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating
eLife 8:e53400.
https://doi.org/10.7554/eLife.53400

Share this article

https://doi.org/10.7554/eLife.53400

Categories and tags

Further reading

    1. Structural Biology and Molecular Biophysics

    Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels

    Ahmad Elbahnsi, John Cowgill ... Lucie Delemotte
    Research Article Updated

    Hyperpolarized-activated and cyclic nucleotide-gated (HCN) channels are the only members of the voltage-gated ion channel superfamily in mammals that open upon hyperpolarization, conferring them pacemaker properties that are instrumental for rhythmic firing of cardiac and neuronal cells. Activation of their voltage-sensor domains (VSD) upon hyperpolarization occurs through a downward movement of the S4 helix bearing the gating charges, which triggers a break in the alpha-helical hydrogen bonding pattern at the level of a conserved Serine residue. Previous structural and molecular simulation studies had however failed to capture pore opening that should be triggered by VSD activation, presumably because of a low VSD/pore electromechanical coupling efficiency and the limited timescales accessible to such techniques. Here, we have used advanced modeling strategies, including enhanced sampling molecular dynamics simulations exploiting comparisons between non-domain swapped voltage-gated ion channel structures trapped in closed and open states to trigger pore gating and characterize electromechanical coupling in HCN1. We propose that the coupling mechanism involves the reorganization of the interfaces between the VSD helices, in particular S4, and the pore-forming helices S5 and S6, subtly shifting the balance between hydrophobic and hydrophilic interactions in a ‘domino effect’ during activation and gating in this region. Remarkably, our simulations reveal state-dependent occupancy of lipid molecules at this emergent coupling interface, suggesting a key role of lipids in hyperpolarization-dependent gating. Our model provides a rationale for previous observations and a possible mechanism for regulation of HCN channels by the lipidic components of the membrane.