Abstract
The sarcoplasmic reticulum calcium pump (SERCA) and its regulator, phospholamban, are essential components of cardiac contractility. Phospholamban modulates contractility by inhibiting SERCA, and this process is dynamically regulated by β-adrenergic stimulation and phosphorylation of phospholamban. Herein we reveal mechanistic insight into how four hereditary mutants of phospholamban, Arg(9) to Cys, Arg(9) to Leu, Arg(9) to His, and Arg(14) deletion, alter regulation of SERCA. Deletion of Arg(14) disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition. Mutation of Arg(9) causes more complex changes in function, where hydrophobic substitutions such as cysteine and leucine eliminate both SERCA inhibition and phospholamban phosphorylation, whereas an aromatic substitution such as histidine selectively disrupts phosphorylation. We demonstrate that the role of Arg(9) in phospholamban function is multifaceted: it is important for inhibition of SERCA, it increases the efficiency of phosphorylation, and it is critical for protein kinase A recognition in the context of the phospholamban pentamer. Given the synergistic consequences on contractility, it is not surprising that the mutants cause lethal, hereditary dilated cardiomyopathy.
Highlights
Heterozygous mutations in the cytoplasmic domain of phospholamban cause lethal dilated cardiomyopathy
We demonstrate that the role of Arg9 in phospholamban function is multifaceted: it is important for inhibition of SERCA, it increases the efficiency of phosphorylation, and it is critical for protein kinase A recognition in the context of the phospholamban pentamer
In the case of PLN mutants (R9C, R9H, R9L, and R9C and Arg14 deletion (R14del)), SERCA dysregulation accounts for the earliest stages of disease, which leads to reduced pumping force, cardiovascular remodeling, and heart failure
Summary
Heterozygous mutations in the cytoplasmic domain of phospholamban cause lethal dilated cardiomyopathy. Results: The mutations alter phospholamban-protein kinase A interactions that are essential for substrate recognition and phosphorylation. Conclusion: Hereditary mutations in phospholamban that prevent phosphorylation by protein kinase A will lead to chronic inhibition of SERCA. Significance: Arginines in the cytoplasmic domain of phospholamban should be considered hot spots for hereditary mutations leading to dilated cardiomyopathy. We reveal mechanistic insight into how four hereditary mutants of phospholamban, Arg to Cys, Arg to Leu, Arg to His, and Arg deletion, alter regulation of SERCA. Deletion of Arg disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition. Given the synergistic consequences on contractility, it is not surprising that the mutants cause lethal, hereditary dilated cardiomyopathy
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