Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

Abstract

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 2+ 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 postphosphorylation, a phenomenon that leads to an ordered shift in the myosin S1 and RLC conformational equilibrium between two distinct states.

Regulatory Light Chains in Cardiac Development and Disease

“…RLC phosphorylation levels are significantly reduced in heart failure patients [ 82 , 83 , 84 ]. Animals in which myocardial infarction is induced by left anterior descending coronary artery ligation display a variation in the changes of RLC phosphorylation levels during heart failure progression.…”

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

“…It is widely accepted that myofilament Ca 2+ sensitivity is regulated via phosphorylation of troponin I (TnI) at Ser 23 and 24 [ 6 , 7 , 8 ]. The phosphorylation of other proteins, such as myosin binding protein C [ 9 ] and regulatory light chain of myosin, also can modulate Ca 2+ sensitivity [ 10 , 11 , 12 ] but to a lesser degree.…”

Phosphomimetic‐mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain

“…The N‐terminal domain of the human ventricular RLC contains a divalent cation binding site and a myosin light chain kinase (MLCK)‐specific phosphorylation site at Ser‐15 . A wealth of studies indicate that phosphorylation of myosin RLC is critical for the normal function of the heart, and that the myocardium containing dephosphorylated RLC has a reduced ability to produce force and maintain cardiac function at physiological levels (reviewed in ). Significantly depressed RLC phosphorylation was reported in heart failure (HF) patients and was also observed in experimental animal models of cardiac disease .…”