Allosteric regulation of SERCA by phosphorylationmediated conformational shift of phospholamban

Martin Gustavsson, Raffaello Verardi, Daniel G. Mullen, Kaustubh R. Mote, Nathaniel J. Traaseth, T. Gopinath, Gianluigi Veglia

Research output: Contribution to journalArticlepeer-review


The membrane protein complex between the sarcoplasmic reticulum Ca 2+-ATPase (SERCA) and phospholamban (PLN) controls Ca2+ transport in cardiomyocytes, thereby modulating cardiac contractility. β-Adrenergic-stimulated phosphorylation of PLN at Ser- 16 enhances SERCA activity via an unknown mechanism. Using solid-state nuclear magnetic resonance spectroscopy, we mapped the physical interactions between SERCA and both unphosphorylated and phosphorylated PLN in membrane bilayers. We found that the allosteric regulation of SERCA depends on the conformational equilibrium of PLN, whose cytoplasmic regulatory domain interconverts between three different states: a ground T state (helical and membrane associated), an excited R state (unfolded and membrane detached), and a B state (extended and enzymebound), which is noninhibitory. Phosphorylation at Ser-16 of PLN shifts the populations toward the B state, increasing SERCA activity. We conclude that PLN's conformational equilibrium is central to maintain SERCA's apparent Ca 2+ affinity within a physiological window. This model represents a paradigm shift in our understanding of SERCA regulation by posttranslational phosphorylation and suggests strategies for designing innovative therapeutic approaches to enhance cardiac muscle contractility.

Original languageEnglish (US)
Pages (from-to)17338-17343
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 22 2013


  • Magic angle spinning
  • Paramagnetic relaxation enhancement
  • Protein-protein interactions
  • Solid-state NMR

ASJC Scopus subject areas

  • General


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