Search

Type 1 ryanodine receptor (RYRl) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation-contraction coupling. Mutations in the RYRl gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of OCR via RYRl. Thus far, >300 mutations in RYRl have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure-function relationship of mutant RYRl, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYRl bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYRl caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYRls were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYRl channel and provide insights into the mechanism of MH caused by the mutations at the NTD. [ABSTRACT FROM AUTHOR]