title: Structure of a mammalian ryanodine receptor.
abstract: Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca(2+)) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation-contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 Å. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca(2+).
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Zalk
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Clarke
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Amédée
authors.initials: A
authors.lastname: des Georges
authors.affiliation: 1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Grassucci
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Filippo
authors.initials: F
authors.lastname: Mancia
authors.affiliation: 1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.affiliation: 1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA [3] Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Frank
authors.affiliation: 1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA [3] Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D002118:Calcium / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D020285:Cryoelectron Microscopy; D003600:Cytosol / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D018482:Muscle, Skeletal / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D002118:Calcium