title: The cardiac ryanodine receptor N-terminal region contains an anion binding site that is targeted by disease mutations.
abstract: Ryanodine receptors (RyRs) are calcium release channels located in the membrane of the endoplasmic and sarcoplasmic reticulum and play a major role in muscle excitation-contraction coupling. The cardiac isoform (RyR2) is the target for >150 mutations that cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and other conditions. Here, we present the crystal structure of the N-terminal region of RyR2 (1-547), an area encompassing 29 distinct disease mutations. The protein folds up in three individual domains, which are held together via a central chloride anion that shields repulsive positive charges. Several disease mutant versions of the construct drastically destabilize the protein. The R420Q disease mutant causes CPVT and ablates chloride binding. The mutation results in reorientations of the first two domains relative to the third domain. These conformational changes likely activate the channel by destabilizing intersubunit interactions that are disrupted upon channel opening.
authors.affiliation: Department of Biochemistry and Molecular Biology and Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Lynn
authors.initials: L
authors.lastname: Kimlicka
authors.forename: Ching-Chieh
authors.initials: CC
authors.lastname: Tung
authors.forename: Anna-Carin Cecilia
authors.initials: AC
authors.lastname: Carlsson
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Lobo
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Yuchi
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
mesh_terms: D000818:Animals; D001665:Binding Sites; D001965:Bromides / Q000737:chemistry; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D020125:Mutation, Missense; D011189:Potassium Chloride / Q000737:chemistry; D017680:Potassium Compounds / Q000737:chemistry; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000235:genetics
chemical_list: D001965:Bromides; D017680:Potassium Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D011189:Potassium Chloride; C039004:potassium bromide