IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29594-w.html
   My bibliography  Save this article

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

Author

Listed:
  • Gamma Chi

    (University of Oxford
    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
    University of Oxford
    Exscientia Ltd.)

  • Nanki Kaur Singh

    (University of Oxford
    University of Oxford)

  • Gavin McKinley

    (University of Oxford
    University of Oxford)

  • Alejandra Fernandez-Cid

    (University of Oxford
    University of Oxford
    Exact Sciences Ltd.)

  • Shubhashish M. M. Mukhopadhyay

    (University of Oxford
    University of Oxford
    Exscientia Ltd.)

  • Nicola A. Burgess-Brown

    (University of Oxford
    University of Oxford
    Exact Sciences Ltd.)

  • Lucie Delemotte

    (KTH)

  • Manuel Covarrubias

    (Sidney Kimmel Medical College at Thomas Jefferson University)

  • Katharina L. Dürr

    (University of Oxford
    University of Oxford
    OMass Therapeutics, Ltd.)

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.

Suggested Citation

  • 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 Ferna, 2022. "Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29594-w
    DOI: 10.1038/s41467-022-29594-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29594-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-29594-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yoshiaki Kise & Go Kasuya & Hiroyuki H. Okamoto & Daichi Yamanouchi & Kan Kobayashi & Tsukasa Kusakizako & Tomohiro Nishizawa & Koichi Nakajo & Osamu Nureki, 2021. "Structural basis of gating modulation of Kv4 channel complexes," Nature, Nature, vol. 599(7883), pages 158-164, November.
    2. Zhe Lu & Angela M. Klem & Yajamana Ramu, 2001. "Ion conduction pore is conserved among potassium channels," Nature, Nature, vol. 413(6858), pages 809-813, October.
    3. Philip Schmiege & Michael Fine & Günter Blobel & Xiaochun Li, 2017. "Human TRPML1 channel structures in open and closed conformations," Nature, Nature, vol. 550(7676), pages 366-370, October.
    4. Lin Tang & Tamer M. Gamal El-Din & Teresa M. Swanson & David C. Pryde & Todd Scheuer & Ning Zheng & William A. Catterall, 2016. "Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs," Nature, Nature, vol. 537(7618), pages 117-121, September.
    5. Stephen B. Long & Xiao Tao & Ernest B. Campbell & Roderick MacKinnon, 2007. "Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment," Nature, Nature, vol. 450(7168), pages 376-382, November.
    6. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    7. Alain J. Labro & Michael F. Priest & Jérôme J. Lacroix & Dirk J. Snyders & Francisco Bezanilla, 2015. "Kv3.1 uses a timely resurgent K+ current to secure action potential repolarization," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Qiansheng Liang & Gamma Chi & Leonardo Cirqueira & Lianteng Zhi & Agostino Marasco & Nadia Pilati & Martin J. Gunthorpe & Giuseppe Alvaro & Charles H. Large & David B. Sauer & Werner Treptow & Manuel , 2024. "The binding and mechanism of a positive allosteric modulator of Kv3 channels," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Martin J. Gunthorpe, 2022. "Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    3. Rían W. Manville & J. Alfredo Freites & Richard Sidlow & Douglas J. Tobias & Geoffrey W. Abbott, 2023. "Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Qiansheng Liang & Gamma Chi & Leonardo Cirqueira & Lianteng Zhi & Agostino Marasco & Nadia Pilati & Martin J. Gunthorpe & Giuseppe Alvaro & Charles H. Large & David B. Sauer & Werner Treptow & Manuel , 2024. "The binding and mechanism of a positive allosteric modulator of Kv3 channels," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Martin J. Gunthorpe, 2022. "Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    3. Philip Schmiege & Linda Donnelly & Nadia Elghobashi-Meinhardt & Chia-Hsueh Lee & Xiaochun Li, 2024. "Structure and inhibition of the human lysosomal transporter Sialin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Rían W. Manville & J. Alfredo Freites & Richard Sidlow & Douglas J. Tobias & Geoffrey W. Abbott, 2023. "Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Léon Faure & Bastien Mollet & Wolfram Liebermeister & Jean-Loup Faulon, 2023. "A neural-mechanistic hybrid approach improving the predictive power of genome-scale metabolic models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Tian Zhu & Merry H. Ma, 2022. "Deriving the Optimal Strategy for the Two Dice Pig Game via Reinforcement Learning," Stats, MDPI, vol. 5(3), pages 1-14, August.
    9. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    11. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    13. Anthony C. Bishop & Glorisé Torres-Montalvo & Sravya Kotaru & Kyle Mimun & A. Joshua Wand, 2023. "Robust automated backbone triple resonance NMR assignments of proteins using Bayesian-based simulated annealing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    14. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    15. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    19. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Justin N. Vaughn & Sandra E. Branham & Brian Abernathy & Amanda M. Hulse-Kemp & Adam R. Rivers & Amnon Levi & William P. Wechter, 2022. "Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29594-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.