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Structure of a mammalian ryanodine receptor

Author

Listed:
  • Ran Zalk

    (Columbia University)

  • Oliver B. Clarke

    (Columbia University)

  • Amédée des Georges

    (Columbia University)

  • Robert A. Grassucci

    (Columbia University
    Howard Hughes Medical Institute, Columbia University)

  • Steven Reiken

    (Columbia University)

  • Filippo Mancia

    (Columbia University)

  • Wayne A. Hendrickson

    (Columbia University
    Columbia University)

  • Joachim Frank

    (Columbia University
    Howard Hughes Medical Institute, Columbia University
    Columbia University)

  • Andrew R. Marks

    (Columbia University
    Columbia University
    Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University)

Abstract

Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca2+) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation–contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 Å. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+.

Suggested Citation

  • Ran Zalk & Oliver B. Clarke & Amédée des Georges & Robert A. Grassucci & Steven Reiken & Filippo Mancia & Wayne A. Hendrickson & Joachim Frank & Andrew R. Marks, 2015. "Structure of a mammalian ryanodine receptor," Nature, Nature, vol. 517(7532), pages 44-49, January.
    • Handle: RePEc:nat:nature:v:517:y:2015:i:7532:d:10.1038_nature13950
    DOI: 10.1038/nature13950
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    Cited by:

    1. Nadège Zanou & Haikel Dridi & Steven Reiken & Tanes Imamura de Lima & Chris Donnelly & Umberto De Marchi & Manuele Ferrini & Jeremy Vidal & Leah Sittenfeld & Jerome N. Feige & Pablo M. Garcia-Roves & , 2021. "Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    2. Robyn T. Rebbeck & Bengt Svensson & Jingyan Zhang & Montserrat Samsó & David D. Thomas & Donald M. Bers & Razvan L. Cornea, 2024. "Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Yuqing Zhang & Shan Han & Congcong Liu & Yuanwen Zheng & Hao Li & Fei Gao & Yuehong Bian & Xin Liu & Hongbin Liu & Shourui Hu & Yuxuan Li & Zi-Jiang Chen & Shigang Zhao & Han Zhao, 2023. "THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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