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Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant

Author

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  • Zhiguang Yuchi

    (The Life Sciences Centre, University of British Columbia)

  • Siobhan M. Wong King Yuen

    (The Life Sciences Centre, University of British Columbia)

  • Kelvin Lau

    (The Life Sciences Centre, University of British Columbia
    Present address: Department of Botany and Plant Biology, University of Geneva, 30 Quai E. Ansermet, 1211 Geneva, Switzerland.)

  • Ainsley Q. Underhill

    (The Life Sciences Centre, University of British Columbia)

  • Razvan L. Cornea

    (Molecular Biology and Biophysics, University of Minnesota)

  • James D. Fessenden

    (Perioperative and Pain Medicine, Brigham and Women's Hospital)

  • Filip Van Petegem

    (The Life Sciences Centre, University of British Columbia)

Abstract

Ryanodine receptors (RyRs) form calcium release channels located in the membranes of the sarcoplasmic and endoplasmic reticulum. RyRs play a major role in excitation-contraction coupling and other Ca2+-dependent signalling events, and consist of several globular domains that together form a large assembly. Here we describe the crystal structures of the SPRY1 and tandem-repeat domains at 1.2–1.5 Å resolution, which reveal several structural elements not detected in recent cryo-EM reconstructions of RyRs. The cryo-EM studies disagree on the position of SPRY domains, which had been proposed based on homology modelling. Computational docking of the crystal structures, combined with FRET studies, show that the SPRY1 domain is located next to FK506-binding protein (FKBP). Molecular dynamics flexible fitting and mutagenesis experiments suggest a hydrophobic cluster within SPRY1 that is crucial for FKBP binding. A RyR1 disease mutation, N760D, appears to directly impact FKBP binding through interfering with SPRY1 folding.

Suggested Citation

  • Zhiguang Yuchi & Siobhan M. Wong King Yuen & Kelvin Lau & Ainsley Q. Underhill & Razvan L. Cornea & James D. Fessenden & Filip Van Petegem, 2015. "Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8947
    DOI: 10.1038/ncomms8947
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