Dysfunctional conformational dynamics of protein kinase a induced by a lethal mutant of phospholamban hinder phosphorylation

Jonggul Kim, Larry R. Masterson, Alessandro Cembran, Raffaello Verardi, Lei Shi, Jiali Gao, Susan S. Taylor, Gianluigi Veglia

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


The dynamic interplay between kinases and substrates is crucial for the formation of catalytically committed complexes that enable phosphoryl transfer. However, a clear understanding on how substrates modulate kinase structural dynamics to control catalytic efficiency is still missing. Here, we used solution NMR spectroscopy to study the conformational dynamics of two complexes of the catalytic subunit of the cAMP-dependent protein kinase A with WT and R14 deletion phospholamban, a lethal human mutant linked to familial dilated cardiomyopathy. Phospholamban is a central regulator of heart muscle contractility, and its phosphorylation by protein kinase A constitutes a primary response to β-adrenergic stimulation. We found that the single deletion of arginine in phospholamban's recognition sequence for the kinase reduces its binding affinity and dramatically reduces phosphorylation kinetics. Structurally, the mutant prevents the enzyme from adopting conformations and motions committed for catalysis, with concomitant reduction in catalytic efficiency. Overall, these results underscore the importance of a well-tuned structural and dynamic interplay between the kinase and its substrates to achieve physiological phosphorylation levels for proper Ca2+ signaling and normal cardiac function.

Original languageEnglish (US)
Pages (from-to)3716-3721
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 24 2015

Bibliographical note

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© 2015, National Academy of Sciences. All rights reserved.


  • Calcium regulation
  • Conformational dynamics
  • NMR
  • Phospholamban
  • Phosphorylation


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