Yadav Sunil, Szczesna-Cordary Danuta
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Ave., RMSB 6113, Miami, FL, 33136, USA.
Biophys Rev. 2017 Feb;9(1):57-64. doi: 10.1007/s12551-017-0248-8. Epub 2017 Jan 25.
Many genetic mutations in sarcomeric proteins, including the cardiac myosin regulatory light chain (RLC) encoded by the MYL2 gene, have been implicated in familial cardiomyopathies. Yet, the molecular mechanisms by which these mutant proteins regulate cardiac muscle mechanics in health and disease remain poorly understood. Evidence has been accumulating that RLC phosphorylation has an influential role in striated muscle contraction and, in addition to the conventional modulation via Ca binding to troponin C, it can regulate cardiac muscle function. In this review, we focus on RLC mutations that have been reported to cause cardiomyopathy phenotypes via compromised RLC phosphorylation and elaborate on pseudo-phosphorylation rescue mechanisms. This new methodology has been discussed as an emerging exploratory tool to understand the role of phosphorylation as well as a genetic modality to prevent/rescue cardiomyopathy phenotypes. Finally, we summarize structural effects post-phosphorylation, a phenomenon that leads to an ordered shift in the myosin S1 and RLC conformational equilibrium between two distinct states.
许多肌节蛋白中的基因突变，包括由MYL2基因编码的心肌肌球蛋白调节轻链（RLC），都与家族性心肌病有关。然而，这些突变蛋白在健康和疾病状态下调节心肌力学的分子机制仍知之甚少。越来越多的证据表明，RLC磷酸化在横纹肌收缩中起重要作用，除了通过钙与肌钙蛋白C结合进行传统调节外，它还可以调节心脏肌肉功能。在这篇综述中，我们聚焦于据报道通过受损的RLC磷酸化导致心肌病表型的RLC突变，并详细阐述假磷酸化挽救机制。这种新方法已被作为一种新兴的探索工具进行讨论，用于理解磷酸化的作用以及作为预防/挽救心肌病表型的一种遗传方式。最后，我们总结了磷酸化后的结构效应，这一现象导致肌球蛋白S1和RLC构象平衡在两种不同状态之间发生有序转变。
