Cryo-EM Structure of the Human Kv3.1 Channel Reveals Gating Control by the Cytoplasmic T1 Domain

Authors

Gamma Chi, University of Oxford
Qiansheng Liang, Thomas Jefferson UniversityFollow
Akshay Sridhar, Science for Life Laboratory
John B Cowgill, Science for Life Laboratory
Kasim Sader, Thermo Fisher Scientific
Mazdak Radjainia, Thermo Fisher Scientific
Pu Qian, Thermo Fisher Scientific
Pablo Castro-Hartmann, Thermo Fisher Scientific
Shayla Venkaya, University of Oxford
Nanki Kaur Singh, University of Oxford
Gavin McKinley, University of Oxford
Alejandra Fernandez-Cid, University of Oxford
Shubhashish M M Mukhopadhyay, University of Oxford
Nicola A Burgess-Brown, University of Oxford
Lucie Delemotte, Science for Life Laboratory
Manuel Covarrubias, Thomas Jefferson UniversityFollow
Katharina L Dürr, University of Oxford,

Document Type

Article

Publication Date

7-15-2022

Comments

This article is the author’s final published version in Nature Communications, Volume 13, Issue 1, July 2022, Article number 4087.

The published version is available at https://doi.org/10.1038/s41467-022-29594-w. Copyright © Chi et al.

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.

Recommended Citation

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; and Dürr, Katharina L, "Cryo-EM Structure of the Human Kv3.1 Channel Reveals Gating Control by the Cytoplasmic T1 Domain" (2022). Department of Neuroscience Faculty Papers. Paper 72.
https://jdc.jefferson.edu/department_neuroscience/72

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English