Faltinova Andrea, Tomaskova Nataša, Antalik Marián, Sevcik Jozef, Zahradnikova Alexandra
Department of Muscle Cell Research, Institute of Molecular Physiology and Genetics of the Centre of Biosciences, Slovak Academy of SciencesBratislava, Slovakia.
Department of Biochemistry and Structural Biology, Institute of Molecular Biology, Slovak Academy of SciencesBratislava, Slovakia.
Front Physiol. 2017 Jun 30;8:443. doi: 10.3389/fphys.2017.00443. eCollection 2017.
Mutations in the cardiac ryanodine receptor (RyR2), the ion channel responsible for release of calcium ions from intracellular stores into cytoplasm, are the cause of several inherited cardiac arrhythmias. At the molecular level, disease symptoms can be mimicked by domain peptides from mutation-prone regions of RyR2 that bind to RyR2 and activate it. Here we show that the domain peptide DP, corresponding to the central helix of the N-terminal region of RyR2, activates the RyR2 channel. Structural modeling of interaction between DP and the N-terminal region of RyR2 in the closed and open conformation provided three plausible structures of the complex. Only one of them could explain the dependence of RyR2 activity on concentration of DP. The structure of the complex was at odds with the previously proposed "domain switch" mechanism of competition between domain peptides and ryanodine receptor domains. Likewise, in structural models of the N-terminal region, the conformational changes induced by DP binding were different from those induced by mutation of central helix amino acids. The activating effect of DP binding and of mutations in the central helix could be explained by their similar effect on the transition energy between the closed and open conformation of RyR2.
心脏兰尼碱受体（RyR2）中的突变是导致几种遗传性心律失常的原因，RyR2是负责将钙离子从细胞内储存释放到细胞质中的离子通道。在分子水平上，来自RyR2易突变区域的结构域肽与RyR2结合并激活它，可模拟疾病症状。在此我们表明，与RyR2 N端区域中央螺旋相对应的结构域肽DP可激活RyR2通道。DP与处于关闭和开放构象的RyR2 N端区域之间相互作用的结构建模提供了该复合物的三种可能结构。其中只有一种能够解释RyR2活性对DP浓度的依赖性。该复合物的结构与先前提出的结构域肽与兰尼碱受体结构域之间竞争的“结构域切换”机制不一致。同样，在N端区域的结构模型中，DP结合诱导的构象变化与中央螺旋氨基酸突变诱导的构象变化不同。DP结合和中央螺旋突变的激活作用可以通过它们对RyR2关闭和开放构象之间转变能量的相似影响来解释。
