Abstract
The SPRY2 domain is one of three repeats of the same fold that are present within the RyR. It has been suggested as a key protein interaction site with dihydropyridine receptors to mediate excitation-contraction coupling in skeletal muscle tissue. RyR1 and RyR2 SPRY2 domains were crystallized and reveal differences with what was thought to be SPRY2 and with several other known SPRY domain structures. Our RyR1 SPRY2 construct (rabbit, 1070-1246) is 43% larger than a previously reported construct (1085-1208), consists of multiple modules, is highly soluble, and is monomeric in nature. Docking of the RyR1 SPRY2 structure places it in between the central rim and the clamp region. The structure of RyR2 SPRY2 (mouse, 1080-1253) and a loss-of-function disease mutant (human, T1107M) causing cardiomyopathy were also determined. The T1107M mutation is buried and causes a large ∼10°C decrease in thermal stability as compared to wildtype and also causes local misfolding of the domain. Finally, RyR1 SPRY2 binding to the DHPR II-III loop is undetectable by isothermal titration calorimetry.
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