title: Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel.
abstract: The skeletal muscle Ca(2+) release channel (RyR1), a homotetramer, regulates the release of Ca(2+) from the sarcoplasmic reticulum to initiate muscle contraction. In this work, we have delineated the RyR1 monomer boundaries in a subnanometer-resolution electron cryomicroscopy (cryo-EM) density map. In the cytoplasmic region of each RyR1 monomer, 36 alpha-helices and 7 beta-sheets can be resolved. A beta-sheet was also identified close to the membrane-spanning region that resembles the cytoplasmic pore structures of inward rectifier K(+) channels. Three structural folds, generated for amino acids 12-565 using comparative modeling and cryo-EM density fitting, localize close to regions implicated in communication with the voltage sensor in the transverse tubules. Eleven of the 15 disease-related residues for these domains are mapped to the surface of these models. Four disease-related residues are found in a basin at the interfaces of these regions, creating a pocket in which the immunophilin FKBP12 can fit. Taken together, these results provide a structural context for both channel gating and the consequences of certain malignant hyperthermia and central core disease-associated mutations in RyR1.
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Irina I
authors.initials: II
authors.lastname: Serysheva
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ludtke
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Baker
authors.forename: Yao
authors.initials: Y
authors.lastname: Cong
authors.forename: Maya
authors.initials: M
authors.lastname: Topf
authors.forename: David
authors.initials: D
authors.lastname: Eramian
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hamilton
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
mesh_terms: D020285:Cryoelectron Microscopy; D003593:Cytoplasm; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel