Disease mutations in the ryanodine receptorN-terminal region couple to a mobile intersubunitinterface

摘要

Ryanodine receptors are large channels that release Ca2+ from the endoplasmic and sarcoplasmicreticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscledisorders, yet detailed mechanisms explaining their effects have been lacking. Here wecompare pseudo-atomic models and propose that channel opening coincides with wideningof a cytoplasmic vestibule formed by the N-terminal region, thus altering an interfacetargeted by 20 disease mutations.We solve crystal structures of several disease mutants thataffect intrasubunit domain–domain interfaces. Mutations affecting intrasubunit ionic pairsalter relative domain orientations, and thus couple to surrounding interfaces. Buried diseasemutations cause structural changes that also connect to the intersubunit contact area. Theseresults suggest that the intersubunit contact region between N-terminal domains is a primetarget for disease mutations, direct or indirect, and we present a model whereby ryanodinereceptors and inositol-1,4,5-trisphosphate receptors are activated by altering domainarrangements in the N-terminal region.