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Cited by 28Ion channel regulation and functionCardiac electrophysiology and arrhythmiasNicotinic Acetylcholine Receptors Study

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Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain

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Chi, Gamma, Liang, Qiansheng, Sridhar, Akshay, Cowgill, John B., Sader, Kasim, Radjainia, Mazdak, Qian, Pu, Castro-Hartmann, Pablo, Venkaya, Shayla, Singh, Nanki Kaur, McKinley, Gavin, Fernandez-Cid, Alejandra, Mukhopadhyay, Shubhashish M. M., Burgess-Brown, Nicola A., Delemotte, Lucie, Covarrubias, Manuel, Dürr, Katharina L.·2022·Nature Communications
DOI 10.1038/s41467-022-29594-wPMC PMC9287412

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Abstract

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 α6 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.

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Metadata

Authors
Chi, G., Liang, Q., Sridhar, A., Cowgill, J. B., Sader, K., Radjainia, M., Qian, P., Castro-Hartmann, P., Venkaya, S., Singh, N. K., McKinley, G., Fernandez-Cid, A., Mukhopadhyay, S. M. M., Burgess-Brown, N. A., Delemotte, L., Covarrubias, M., & Dürr, K. L.
Affiliations
  • University of Oxford (GB)
  • Thomas Jefferson University (US)
  • Science for Life Laboratory (SE)
  • Thermo Fisher Scientific (Netherlands) (NL)
Corresponding author
Dürr, Katharina L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-07-15
Volume
13
Issue
1
Pages
4087-4087
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-29594-w
PMC
PMC9287412
OpenAlex
W4285589102
Cited by
28
References
2
Citations by year
2026: 5 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 4
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • McGill University
  • Wellcome Trust (106169/Z/14/Z, 106169, 115766, 060208/Z/00/Z, 093305, 093305/Z/10/Z)
  • Diamond Light Source
  • European Federation of Pharmaceutical Industries and Associations (115766, 875510)
  • European Commission (HORIZON2020, 898762, 115766, 875510)
  • Partnership for Advanced Computing in Europe AISBL
  • Vetenskapsrådet (VR 2018, 2018-, 2018-04905)
  • Science for Life Laboratory
  • Innovative Medicines Initiative (875510, 115766, No. 115766)
  • Medical Research Council (MC_PC_17137, MC_PC_17136)
  • National Supercomputing Center, Korea Institute of Science and Technology Information
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
KCNC1, potassium channel gating, S4-S5 linker, gating kinetics, fast-spiking neurons, epilepsy, electrostatic interactions, drug target design
MeSH terms
Humans, Ion Channel Gating, Protein Structure, Secondary, Cryoelectron Microscopy, Shaw Potassium Channels, Static Electricity, Molecular Dynamics Simulation

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