Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain

Kelvin Lau and Filip Van Petegem ()
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Kelvin Lau: The Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall
Filip Van Petegem: The Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Ryanodine receptors (RyRs) form channels responsible for the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum. The SPRY2 domain in the skeletal muscle isoform (RyR1) has been proposed as a direct link with L-type calcium channels (CaV1.1), allowing for direct mechanical coupling between plasma membrane depolarization and Ca2+ release. Here we present the crystal structures of the SPRY2 domain from RyR1 and RyR2 at 1.34–1.84 Å resolution. They form two antiparallel β sheets establishing a core, and four additional modules of which several are required for proper folding. A buried disease mutation, linked to hypertrophic cardiomyopathy and loss-of-function, induces local misfolding and strong destabilization. Isothermal titration calorimetry experiments negate the RyR1 SPRY2 domain as the major link with CaV1.1. Instead, docking into full-length RyR1 cryo-electron microscopy maps suggests that the SPRY2 domain forms a link between the N-terminal gating ring and the clamp region.

Date: 2014
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DOI: 10.1038/ncomms6397

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