IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48536-2.html
   My bibliography  Save this article

Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation

Author

Listed:
  • Karin E. J. Rödström

    (University of Oxford
    University of Oxford
    University of Oxford
    University of Oxford)

  • Alexander Cloake

    (University of Oxford)

  • Janina Sörmann

    (University of Oxford
    University of Oxford)

  • Agnese Baronina

    (University of Oxford)

  • Kathryn H. M. Smith

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Ashley C. W. Pike

    (University of Oxford)

  • Jackie Ang

    (University of Oxford)

  • Peter Proks

    (University of Oxford
    University of Oxford)

  • Marcus Schewe

    (Kiel University)

  • Ingelise Holland-Kaye

    (University of Oxford)

  • Simon R. Bushell

    (University of Oxford)

  • Jenna Elliott

    (University of Oxford)

  • Els Pardon

    (Vrije Universiteit Brussel
    VIB)

  • Thomas Baukrowitz

    (Kiel University)

  • Raymond J. Owens

    (The Rosalind Franklin Institute
    University of Oxford)

  • Simon Newstead

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Jan Steyaert

    (Vrije Universiteit Brussel
    VIB)

  • Elisabeth P. Carpenter

    (University of Oxford
    University of Oxford)

  • Stephen J. Tucker

    (University of Oxford
    University of Oxford
    University of Oxford)

Abstract

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Suggested Citation

  • Karin E. J. Rödström & Alexander Cloake & Janina Sörmann & Agnese Baronina & Kathryn H. M. Smith & Ashley C. W. Pike & Jackie Ang & Peter Proks & Marcus Schewe & Ingelise Holland-Kaye & Simon R. Bushe, 2024. "Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48536-2
    DOI: 10.1038/s41467-024-48536-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48536-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-48536-2?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. Prafulla Aryal & Firdaus Abd-Wahab & Giovanna Bucci & Mark S. P. Sansom & Stephen J. Tucker, 2014. "A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel," Nature Communications, Nature, vol. 5(1), pages 1-9, September.
    2. Purushotham Selvakumar & Ana I. Fernández-Mariño & Nandish Khanra & Changhao He & Alice J. Paquette & Bing Wang & Ruiqi Huang & Vaughn V. Smider & William J. Rice & Kenton J. Swartz & Joel R. Meyerson, 2022. "Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Stephen G. Brohawn & Ernest B. Campbell & Roderick MacKinnon, 2014. "Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel," Nature, Nature, vol. 516(7529), pages 126-130, December.
    Full references (including those not matched with items on IDEAS)

    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. Toby S. Turney & Vivian Li & Stephen G. Brohawn, 2022. "Structural Basis for pH-gating of the K+ channel TWIK1 at the selectivity filter," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Marcos Matamoros & Xue Wen Ng & Joshua B. Brettmann & David W. Piston & Colin G. Nichols, 2023. "Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Philipp A. M. Schmidpeter & John T. Petroff & Leila Khajoueinejad & Aboubacar Wague & Cheryl Frankfater & Wayland W. L. Cheng & Crina M. Nimigean & Paul M. Riegelhaupt, 2023. "Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Xiaofen Liu & Weiwei Wang, 2023. "Asymmetric gating of a human hetero-pentameric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    5. Ben Sorum & Trevor Docter & Vincent Panico & Robert A. Rietmeijer & Stephen G. Brohawn, 2024. "Tension activation of mechanosensitive two-pore domain K+ channels TRAAK, TREK-1, and TREK-2," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    6. 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.
    7. Ruo-Xu Gu & Bert L. Groot, 2023. "Central cavity dehydration as a gating mechanism of potassium channels," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Berke Türkaydin & Marcus Schewe & Elena Barbara Riel & Friederike Schulz & Johann Biedermann & Thomas Baukrowitz & Han Sun, 2024. "Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Jonathan Mount & Grigory Maksaev & Brock T. Summers & James A. J. Fitzpatrick & Peng Yuan, 2022. "Structural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Martina Nicoletti & Letizia Chiodo & Alessandro Loppini, 2021. "Biophysics and Modeling of Mechanotransduction in Neurons: A Review," Mathematics, MDPI, vol. 9(4), pages 1-32, February.
    11. Yuanyue Shan & Mengmeng Zhang & Meiyu Chen & Xinyi Guo & Ying Li & Mingfeng Zhang & Duanqing Pei, 2024. "Activation mechanisms of dimeric mechanosensitive OSCA/TMEM63 channels," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Zhihui He & Yonghui Zhao & Michael J. Rau & James A. J. Fitzpatrick & Rajan Sah & Hongzhen Hu & Peng Yuan, 2023. "Structural and functional analysis of human pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    13. Mingfeng Zhang & Yuanyue Shan & Charles D. Cox & Duanqing Pei, 2023. "A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity," Nature Communications, Nature, vol. 14(1), pages 1-9, 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:15:y:2024:i:1:d:10.1038_s41467-024-48536-2. 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.