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

Proceedings of the National Academy of Sciences of the United States of America
Jonggul KimGianluigi Veglia

Abstract

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 level...Continue Reading

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Citations

Aug 8, 2015·Journal of the American Chemical Society·Kody J MoleschiGiuseppe Melacini
Apr 26, 2016·Chemical Reviews·Stephen Boulton, Giuseppe Melacini
Apr 14, 2017·The Journal of Physical Chemistry. B·T GopinathGianluigi Veglia
Sep 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Wen-Ting ChuJin Wang
Sep 16, 2015·The Journal of Biological Chemistry·Bryan VanSchouwenGiuseppe Melacini
Apr 12, 2017·Proceedings of the National Academy of Sciences of the United States of America·George P LisiJ Patrick Loria
Apr 25, 2017·Science Advances·Jonggul KimGianluigi Veglia
Feb 27, 2019·Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation·C C CheungA D Krahn
Dec 18, 2018·PLoS Computational Biology·Wojciech PotrzebowskiIngemar Andre
Feb 4, 2019·Chemistry and Physics of Lipids·Evgeniy S SalnikovBurkhard Bechinger
Aug 18, 2021·Journal of Molecular Biology·Bryan VanSchouwenGiuseppe Melacini

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