IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-21141-3.html
   My bibliography  Save this article

Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM

Author

Listed:
  • Kellie A. Woll

    (University of British Columbia, Department of Biochemistry and Molecular Biology, Life Sciences Centre)

  • Omid Haji-Ghassemi

    (University of British Columbia, Department of Biochemistry and Molecular Biology, Life Sciences Centre)

  • Filip Van Petegem

    (University of British Columbia, Department of Biochemistry and Molecular Biology, Life Sciences Centre)

Abstract

Ryanodine Receptors (RyRs) are massive channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological ‘intermediate’ conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions.

Suggested Citation

  • Kellie A. Woll & Omid Haji-Ghassemi & Filip Van Petegem, 2021. "Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21141-3
    DOI: 10.1038/s41467-021-21141-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-21141-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-21141-3?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
    ---><---

    Citations

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


    Cited by:

    1. Michael J. Maxwell & Chris Thekkedam & Cedric Lamboley & Yanni K.-Y. Chin & Theo Crawford & Jennifer J. Smith & Junyu Liu & Xinying Jia & Irina Vetter & Derek R. Laver & Bradley S. Launikonis & Angela, 2023. "A bivalent remipede toxin promotes calcium release via ryanodine receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Takuya Kobayashi & Akihisa Tsutsumi & Nagomi Kurebayashi & Kei Saito & Masami Kodama & Takashi Sakurai & Masahide Kikkawa & Takashi Murayama & Haruo Ogawa, 2022. "Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations," Nature Communications, Nature, vol. 13(1), pages 1-15, 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:12:y:2021:i:1:d:10.1038_s41467-021-21141-3. 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.