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Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization- dependent gating
KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-7497-9448
Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA..
Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA.;Univ Wisconsin, Grad Program Biophys, Madison, WI USA..ORCID iD: 0000-0002-7968-8359
Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA..
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e53400Article in journal (Refereed) Published
Abstract [en]

In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltagesensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (similar to 20 mu s) 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.

Place, publisher, year, edition, pages
NLM (Medline) , 2019. Vol. 8, article id e53400
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Biological Sciences
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URN: urn:nbn:se:kth:diva-266207DOI: 10.7554/eLife.53400ISI: 000502276500001PubMedID: 31774399Scopus ID: 2-s2.0-85076385930OAI: oai:DiVA.org:kth-266207DiVA, id: diva2:1383998
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QC 20200109

Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09Bibliographically approved

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Kasimova, Marina A.Delemotte, Lucie

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