Computational Analysis of Binding Interactions between the Ryanodine Receptor Type 2 and Calmodulin
Computational Analysis of Binding Interactions between the Ryanodine Receptor Type 2 and Calmodulin
复制标题
DOI：
10.1021/acs.jpcb.1c03896
复制
发表时间：
2021-09-17
影响因子：
3.3
通讯作者：
Shiferaw, Yohannes
中科院分区：
文献类型：
--
作者：
Greene, D'Artagnan;Barton, Michael;Shiferaw, Yohannes
心脏2型兰尼碱受体（RyR 2）的突变与多种心律失常有关，如儿茶酚胺能多形性室性心动过速（CPVT）。RyR 2受钙调蛋白（CaM）调节，破坏其相互作用的突变可导致异常钙释放，导致心律失常。最近的研究表明，增加RyR 2-CaM结合亲和力可以将有缺陷的CPVT相关RyR 2通道恢复到接近野生型的行为。然而，确定在RyR 2-CaM结合界面的结合亲和力的相互作用还没有很好地理解。在这项研究中，我们确定的关键领域和相互作用，包括几个新的相互作用，参与结合钙调素RyR 2。此外，我们的野生型和V3599 K突变体之间的比较表明，RyR 2-CaM结合亲和力如何可以通过改变中央和N-末端叶结合接触钙调素增加。这种计算方法为RyR 2-CaM结合界面突变的影响提供了新的见解，并且可能在未来治疗心律失常的药物设计中找到实用性。
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.