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

Gamma Chi, Qiansheng Liang, Akshay Sridhar, John B. Cowgill, Kasim Sader, Mazdak Radjainia, Pu Qian, Pablo Castro-Hartmann, Shayla Venkaya, Nanki Kaur Singh, Gavin McKinley, Alejandra Fernandez-Cid, Shubhashish M. M. Mukhopadhyay, Nicola A. Burgess-Brown, Lucie Delemotte, Manuel Covarrubias and Katharina L. Dürr ()
Additional contact information
Gamma Chi: University of Oxford
Qiansheng Liang: Sidney Kimmel Medical College at Thomas Jefferson University
Akshay Sridhar: KTH
John B. Cowgill: KTH
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: KTH
Manuel Covarrubias: Sidney Kimmel Medical College at Thomas Jefferson University
Katharina L. Dürr: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29594-w

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DOI: 10.1038/s41467-022-29594-w

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