{"entity": "publication", "iuid": "726298bd291b486f9458031f71d6d2d7", "timestamp": "2026-04-20T03:13:26.907Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/726298bd291b486f9458031f71d6d2d7.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/726298bd291b486f9458031f71d6d2d7"}}, "title": "Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating.", "authors": [{"family": "Kasimova", "given": "Marina A", "initials": "MA", "orcid": "0000-0002-7497-9448", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4e9380d1e1db4c669ac85f476eb8c3d5.json"}}, {"family": "Tewari", "given": "Debanjan", "initials": "D"}, {"family": "Cowgill", "given": "John B", "initials": "JB", "orcid": "0000-0002-7968-8359", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/861488d03cd8493388b75eab8476381d.json"}}, {"family": "Ursuleaz", "given": "Willy Carrasquel", "initials": "WC"}, {"family": "Lin", "given": "Jenna L", "initials": "JL"}, {"family": "Delemotte", "given": "Lucie", "initials": "L", "orcid": "0000-0002-0828-3899", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/87eaf619d7bd487ebdbe68c46b827e66.json"}}, {"family": "Chanda", "given": "Baron", "initials": "B", "orcid": "0000-0003-4954-7034", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d66119f97dd7443287276dea2fe6d844.json"}}], "type": "journal article", "published": "2019-11-27", "journal": {"title": "Elife", "issn": "2050-084X", "issn-l": "2050-084X", "volume": "8", "issue": null, "pages": null}, "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 \u03bcs) 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.", "doi": "10.7554/eLife.53400", "pmid": "31774399", "labels": {"Lucie Delemotte": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "53400"}, {"db": "pmc", "key": "PMC6904216"}], "notes": [], "created": "2020-11-19T08:57:19.232Z", "modified": "2022-11-04T11:32:15.763Z"}