Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 7, Pages 2735-2740Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1013987108
Keywords
SERCA; ventricular dilatation; calcium regulation; heart failure; membrane proteins
Categories
Funding
- National Institutes of Health [HL80081, GM072701, HL09536, T32DE007288, HL092321, EB006061]
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The regulatory interaction of phospholamban (PLN) with Ca2+-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.
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