puc-header

Helix Breaking Transition in the S4 of HCN Channel is Critical for Hyperpolarization-Dependent Gating

44 Pages Posted: 15 Oct 2019 Publication Status: Review Complete

See all articles by Marina A. Kasimova

Marina A. Kasimova

Royal Institute of Technology (KTH) - Science for Life Laboratory

Debanjan Tewari

University of Wisconsin - Madison - Department of Neuroscience

John Cowgill

University of Wisconsin - Madison - Department of Neuroscience

Willy Carrasquel Ursulaez

University of Wisconsin - Madison - Department of Neuroscience

Jenna Lin

University of Wisconsin - Madison - Department of Neuroscience

Lucie Delemotte

Royal Institute of Technology (KTH) - Science for Life Laboratory

Baron Chanda

University of Wisconsin - Madison - Department of Neuroscience

More...

Abstract

HCN channels, unlike other members of the VGIC superfamily, open upon hyperpolarization rather than depolarization. Structural and functional analyses reveal that the voltage-sensor of these channels are unique but the mechanisms that lead to inward rectification remain poorly understood. Here, using all-atom molecular dynamics simulations under hyperpolarization conditions, we report that the S4 voltage-sensor of HCN channels initially moves downward but, upon transfer of the last gating charge, breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane plane. Substitution of the serine at the breakpoint with a hydrophobic residue favors outward rectification but this effect can be reversed by inserting a serine in an adjacent position. We find that the gating polarity strongly correlates with hydrophilicity and helical turn propensity of the substituents at the breakpoint. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.

Keywords: Gating polarity, voltage sensing, MD simulations, Hyperpolarization activation, Free energy perturbation, Anton simulations, inward rectification, bipolar chimeras

Suggested Citation

Kasimova, Marina A. and Tewari, Debanjan and Cowgill, John and Carrasquel Ursulaez, Willy and Lin, Jenna and Delemotte, Lucie and Chanda, Baron, Helix Breaking Transition in the S4 of HCN Channel is Critical for Hyperpolarization-Dependent Gating (October 12, 2019). Available at SSRN: https://ssrn.com/abstract=3468492 or http://dx.doi.org/10.2139/ssrn.3468492
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Marina A. Kasimova

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Debanjan Tewari

University of Wisconsin - Madison - Department of Neuroscience ( email )

1111 Highland Ave.
Room 5505 WIMR-II
Madison, WI 53705
United States

John Cowgill

University of Wisconsin - Madison - Department of Neuroscience ( email )

1111 Highland Ave.
Room 5505 WIMR-II
Madison, WI 53705
United States

Willy Carrasquel Ursulaez

University of Wisconsin - Madison - Department of Neuroscience ( email )

1111 Highland Ave.
Room 5505 WIMR-II
Madison, WI 53705
United States

Jenna Lin

University of Wisconsin - Madison - Department of Neuroscience ( email )

1111 Highland Ave.
Room 5505 WIMR-II
Madison, WI 53705
United States

Lucie Delemotte

Royal Institute of Technology (KTH) - Science for Life Laboratory ( email )

Stockholm, SE-100 44
Sweden

Baron Chanda (Contact Author)

University of Wisconsin - Madison - Department of Neuroscience ( email )

1111 Highland Ave.
Room 5505 WIMR-II
Madison, WI 53705
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
767
Downloads
35
PlumX Metrics