Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating
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
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
- Richard W Aldrich, The University of Texas at Austin, United States
Version history
- Received: November 7, 2019
- Accepted: November 19, 2019
- Accepted Manuscript published: November 27, 2019 (version 1)
- 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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