Computational Analysis of Binding Interactions between the Ryanodine Receptor Type 2 and Calmodulin
- D’Artagnan Greene*
- Michael BartonMichael BartonDepartment of Physics, California State University, Northridge, California 91330, United StatesMore by Michael Barton
- Tyler Luchko
- , and
- Yohannes ShiferawYohannes ShiferawDepartment of Physics, California State University, Northridge, California 91330, United StatesMore by Yohannes Shiferaw
Mutations in the cardiac ryanodine receptor type 2 (RyR2) have been linked to a variety of cardiac arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). RyR2 is regulated by calmodulin (CaM), and mutations that disrupt their interaction can cause aberrant calcium release, leading to an arrhythmia. It was recently shown that increasing the RyR2–CaM binding affinity could rescue a defective CPVT-related RyR2 channel to near wild-type behavior. However, the interactions that determine the binding affinity at the RyR2–CaM binding interface are not well understood. In this study, we identify the key domains and interactions, including several new interactions, involved in the binding of CaM to RyR2. Also, our comparison between the wild-type and V3599K mutant suggests how the RyR2–CaM binding affinity can be increased via a change in the central and N-terminal lobe binding contacts for CaM. This computational approach provides new insights into the effect of a mutation at the RyR2–CaM binding interface, and it may find utility in drug design for the future treatment of cardiac arrhythmias.
This article is cited by 3 publications.
- Jules Nde, Pengzhi Zhang, M. Neal Waxham, Margaret S. Cheung. Experiment and Simulation Reveal Residue Details for How Target Binding Tunes Calmodulin’s Calcium-Binding Properties. The Journal of Physical Chemistry B 2023, 127
, 2900-2908. https://doi.org/10.1021/acs.jpcb.2c08734
- D’Artagnan Greene, Michael Barton, Tyler Luchko, Yohannes Shiferaw. Molecular Dynamics Simulations of the Cardiac Ryanodine Receptor Type 2 (RyR2) Gating Mechanism. The Journal of Physical Chemistry B 2022, 126
, 9790-9809. https://doi.org/10.1021/acs.jpcb.2c03031
- Angelos Thanassoulas, Vyronia Vassilakopoulou, Brian L. Calver, Luke Buntwal, Adrian Smith, Christopher Lai, Iris Kontogianni, Evangelia Livaniou, George Nounesis, F. Anthony Lai, Michail Nomikos. Life-threatening arrhythmogenic CaM mutations disrupt CaM binding to a distinct RyR2 CaM-binding pocket. Biochimica et Biophysica Acta (BBA) - General Subjects 2023, 1867
, 130313. https://doi.org/10.1016/j.bbagen.2023.130313