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Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Univ Oxford, Ctr Med Discovery, Nuffield Dept Med, Roosevelt Dr, Oxford OX3 7DQ, England.;Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Roosevelt Dr, Oxford OX3 7DQ, England..
Thomas Jefferson Univ, Dept Neurosci & Vickie, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA.;Thomas Jefferson Univ, Jack Farber Inst Neurosci, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA..
KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.ORCID iD: 0000-0002-7968-8359
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 4087Article in journal (Refereed) Published
Abstract [en]

Kv3 channels have distinctive gating kinetics tailored for rapid repolarization in fast-spiking neurons. Malfunction of this process due to genetic variants in the KCNC1 gene causes severe epileptic disorders, yet the structural determinants for the unusual gating properties remain elusive. Here, we present cryo-electron microscopy structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic tetramerization domain T1 which facilitates interactions with C-terminal axonal targeting motif and key components of the gating machinery. Additional interactions between S1/S2 linker and turret domain strengthen the interface between voltage sensor and pore domain. Supported by molecular dynamics simulations, electrophysiological and mutational analyses, we identify several residues in the S4/S5 linker which influence the gating kinetics and an electrostatic interaction between acidic residues in alpha 6 of T1 and R449 in the pore-flanking S6T helices. These findings provide insights into gating control and disease mechanisms and may guide strategies for the design of pharmaceutical drugs targeting Kv3 channels. Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.

Place, publisher, year, edition, pages
Springer Nature , 2022. Vol. 13, no 1, article id 4087
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Biophysics
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URN: urn:nbn:se:kth:diva-315942DOI: 10.1038/s41467-022-29594-wISI: 000826101400018PubMedID: 35840580Scopus ID: 2-s2.0-85134215136OAI: oai:DiVA.org:kth-315942DiVA, id: diva2:1684694
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QC 20230612

Available from: 2022-07-28 Created: 2022-07-28 Last updated: 2023-06-12Bibliographically approved

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Sridhar, AkshayCowgill, JohnDelemotte, Lucie

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