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

Zhiguang Yuchi, Siobhan M. Wong King Yuen, Kelvin Lau, Ainsley Q. Underhill, Razvan L. Cornea, James D. Fessenden () and Filip Van Petegem ()
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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
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

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8947

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