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

Kim N Ha1, Larry R Masterson, Zhanjia Hou

  • 1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 2, 2011
PubMed

Insights

The phospholamban (PLN) R9C mutation stabilizes PLN pentamers, disrupting calcium uptake and heart function. Oxidative stress worsens these cardiotoxic effects, revealing a new role for PLN pentamers in calcium homeostasis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Protein Biochemistry

Background:

  • Phospholamban (PLN) regulates sarcoplasmic reticulum calcium uptake, impacting heart muscle contractility.
  • A specific PLN mutation (R9C) is linked to human dilated cardiomyopathy and premature death.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the PLN R9C mutation causes dilated cardiomyopathy.
  • To elucidate the role of PLN pentamer stability and oxidative stress in cardiac dysfunction.

Main Methods:

  • In vitro and live-cell biochemical and biophysical techniques.
  • Analysis of PLN pentamer assembly, Ca(2+)-ATPase interaction, and protein kinase A phosphorylation.
  • Assessment of effects under varying oxidative conditions.

Main Results:

  • The R9C mutation stabilizes the PLN pentamer through disulfide bridge formation.
  • This stabilization inhibits PLN binding to Ca(2+)-ATPase and phosphorylation by protein kinase A.
  • Oxidative stress exacerbates the cardiotoxic effects of the PLN(R9C) mutant.

Conclusions:

  • The PLN R9C mutation promotes cardiac dysfunction by stabilizing PLN pentamers and impairing calcium regulation.
  • Oxidative stress plays a significant role in the pathogenesis of PLN(R9C)-associated cardiomyopathy.
  • PLN pentamers have a direct regulatory role in calcium homeostasis, beyond monomer storage.

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