Investigating the inter-subunit/subdomain interactions and motions relevant to disease mutations in the N-terminal domain of ryanodine receptors by molecular dynamics simulation

Proteins
Wenjun Zheng, Zheng Liu

Abstract

The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles, and numerous disease mutations have been identified in two RyR isoforms, RyR1 in skeletal muscle and RyR2 in cardiac muscle. A deep understanding of the activation/regulation mechanisms of RyRs has been hampered by the shortage of high-resolution structures and dynamic information for this giant tetrameric complex in different functional states. Toward elucidating the molecular mechanisms of disease mutations in RyRs, we performed molecular dynamics simulation of the N-terminal domain (NTD) which is not only the best-resolved structural component of RyRs, but also a hotspot of disease mutations. First, we simulated the tetrameric NTD of wild-type RyR1 and three disease mutants (K155E, R157Q, and R164Q) that perturb the inter-subunit interfaces. Our simulations identified a dynamic network of salt bridges involving charged residues at the inter-subunit/subdomain interfaces and disease-mutation sites. By perturbing this key network, the above three mutations result in greater flexibility with the highest inter-subunit opening probability for R157Q. Next, we simulated the monomeric NTD of RyR2 in the presence or absence of a central Cl(-) anion w...Continue Reading

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Citations

Dec 17, 2019·The Journal of General Physiology·Toshiko YamazawaMasamitsu Iino
Feb 11, 2020·Journal of Muscle Research and Cell Motility·Haruo OgawaTakashi Murayama
Sep 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vladena Bauerová-HlinkováJacob A Bauer

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