Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A

Delaine K. Ceholski, Catharine A. Trieber, Charles F.B. Holmes, Howard S. Young

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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, Arg9 to Cys, Arg9 to Leu, Arg9 to His, and Arg14 deletion, alter regulation of SERCA. Deletion of Arg14 disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition. Mutation of Arg9 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 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. Given the synergistic consequences on contractility, it is not surprising that the mutants cause lethal, hereditary dilated cardiomyopathy.

Original languageEnglish
Pages (from-to)26596-26605
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number32
DOIs
StatePublished - 3 Aug 2012
Externally publishedYes

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