IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v599y2021i7883d10.1038_s41586-021-03935-z.html
   My bibliography  Save this article

Structural basis of gating modulation of Kv4 channel complexes

Author

Listed:
  • Yoshiaki Kise

    (The University of Tokyo)

  • Go Kasuya

    (Jichi Medical University)

  • Hiroyuki H. Okamoto

    (The University of Tokyo)

  • Daichi Yamanouchi

    (The University of Tokyo)

  • Kan Kobayashi

    (The University of Tokyo
    Peptidream)

  • Tsukasa Kusakizako

    (The University of Tokyo)

  • Tomohiro Nishizawa

    (The University of Tokyo
    Yokohama City University)

  • Koichi Nakajo

    (Jichi Medical University)

  • Osamu Nureki

    (The University of Tokyo)

Abstract

Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart1,2. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary β-subunits—intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)—to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials1–5. However, the modulatory mechanisms of Kv4 channel complexes remain largely unknown. Here we report cryo-electron microscopy structures of the Kv4.2–DPP6S–KChIP1 dodecamer complex, the Kv4.2–KChIP1 and Kv4.2–DPP6S octamer complexes, and Kv4.2 alone. The structure of the Kv4.2–KChIP1 complex reveals that the intracellular N terminus of Kv4.2 interacts with its C terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. In consequence, KChIP1 would prevent N-type inactivation and stabilize the S6 conformation to modulate gating of the S6 helices within the tetramer. By contrast, unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1–S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2–KChIP1–DPP6S ternary complex. Thus, our data suggest that two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:599:y:2021:i:7883:d:10.1038_s41586-021-03935-z
    DOI: 10.1038/s41586-021-03935-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-021-03935-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-021-03935-z?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
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    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. 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.
    4. Grace D. Galles & Daniel T. Infield & Colin J. Clark & Marcus L. Hemshorn & Shivani Manikandan & Frederico Fazan & Ali Rasouli & Emad Tajkhorshid & Jason D. Galpin & Richard B. Cooley & Ryan A. Mehl &, 2023. "Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells," Nature Communications, Nature, vol. 14(1), pages 1-12, 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:nature:v:599:y:2021:i:7883:d:10.1038_s41586-021-03935-z. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.