Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A

Kim N. Ha, Larry R. Mastersona, Zhanjia Hou, Raffaello Verardi, Naomi Walsh, Gianluigi Veglia, Seth L. Robia

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The regulatory interaction of phospholamban (PLN) with Ca 2+-ATPase controls the uptake of calcium into the sarcoplasmic reticulum, modulating heart muscle contractility. A missense mutation in PLN cytoplasmic domain (R9C) triggers dilated cardiomyopathy in humans, leading to premature death. Using a combination of biochemical and biophysical techniques both in vitro and in live cells, we show that the R9C mutation increases the stability of the PLN pentameric assembly via disulfide bridge formation, preventing its binding to Ca2+-ATPase as well as phosphorylation by protein kinase A. These effects are enhanced under oxidizing conditions, suggesting that oxidative stress may exacerbate the cardiotoxic effects of the PLNR9C mutant. These results reveal a regulatory role of the PLN pentamer in calcium homeostasis, going beyond the previously hypothesized role of passive storage for active monomers.

Original languageEnglish (US)
Pages (from-to)2735-2740
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number7
DOIs
StatePublished - Feb 15 2011

Keywords

  • Calcium regulation
  • Heart failure
  • Membrane proteins
  • SERCA
  • Ventricular dilatation

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