Subnanometer-Resolution Electron Cryomicroscopy-Based Domain Models for the Cytoplasmic Region of Skeletal Muscle RyR Channel

The skeletal muscle Ca²⁺ release channel (RyR1), a homotetramer, regulates the release of Ca²⁺ 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 t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-07, Vol.105 (28), p.9610-9615
Main Authors: Serysheva, Irina I., Ludtke, Steven J., Baker, Matthew L., Cong, Yao, Topf, Maya, Eramian, David, Sali, Andrej, Hamilton, Susan L., Chiu, Wah
Format: Article
Language:English
Subjects:
Allosteric regulation
Amino acids
Biological Sciences
Calcium
Cells
Connected regions
Cryoelectron Microscopy
Crystal structure
Cytoplasm
Membranes
Modeling
Models, Molecular
Molecular structure
Muscle, Skeletal - chemistry
Musculoskeletal system
Mutation
Protein Structure, Secondary
Protein Structure, Tertiary
Receptors
Ryanodine Receptor Calcium Release Channel - chemistry
Sarcoplasmic reticulum
Skeletal muscle
Three dimensional modeling
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Summary:The skeletal muscle Ca²⁺ release channel (RyR1), a homotetramer, regulates the release of Ca²⁺ 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 α-helices and 7 β-sheets can be resolved. A β-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0803189105