Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca 2؉ . Ca 2؉ is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca 2؉ transient by activation of a class of Ca 2؉ release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca 2؉ -ATPases (SERCAs) to terminate the Ca 2؉ transient. Mutations in the type 1 ryanodine receptor gene, RYR1, are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and central core disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR NTD) at 2.5 Å. The RyR NTD structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP 3Rsup), but lacks most of the long helix-turn-helix segment of the ''arm'' domain in IP 3Rsup. The N-terminal -trefoil fold, found in both RyR and IP3R, is likely to play a critical role in regulatory mechanisms in this channel family. A disease-associated mutation ''hot spot'' loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR NTD, supporting previously described mechanisms whereby mutations perturb protein-protein interactions.nuclear magnetic resonance ͉ X-ray crystal structure ͉ malignant hyperthermia ͉ central core disease
Ryanodine receptors (RyRs) are the largest known ion channels. They are Ca 2+ release channels found primarily on the sarcoplasmic reticulum of myocytes. Several hundred mutations in RyRs are associated with skeletal or cardiomyocyte disease in humans. Many of these mutations can now be mapped onto the high resolution structures of individual RyR domains and on full-length tetrameric cryo-electron microscopy structures. A closely related Ca 2+ release channel, the inositol 1,4,5-trisphospate receptor (IP 3 R), shows a conserved structural architecture at the N-terminus, suggesting that both channels evolved from an ancestral unicellular RyR/ IP 3 R. The functional insights provided by recent structural studies for both channels will aid in the development of rationale treatments for a myriad of Ca 2+ -signaled malignancies.
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