Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel
Abstract
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.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- July 2008
- DOI:
- 10.1073/pnas.0803189105
- Bibcode:
- 2008PNAS..105.9610S
- Keywords:
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- Ca2+ release channels;
- cryo-EM;
- 3D Structure;
- modeling;
- Biological Sciences:Biophysics