ArticleProceedings of the National Academy of Sciences of the United States of America2015
Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- Phospholamban R14del disease: The past, the present and the future.Frontiers in cardiovascular medicine · 2023Review
- A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction.Nature structural & molecular biology · 2022Article
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy.eLife · 2022Article
- Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers.Cell reports · 2021Article
- Article
- Phospholamban cardiomyopathy: a Canadian perspective on a unique population.Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation · 2019Article
- Globally correlated conformational entropy underlies positive and negative cooperativity in a kinase's enzymatic cycle.Nature communications · 2019Article
- Bayesian inference of protein conformational ensembles from limited structural data.PLoS computational biology · 2018Article
- Supramolecular Organization of Apolipoprotein-A-I-Derived Peptides within Disc-like Arrangements.Biophysical journal · 2018Article
- Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers.Biochimica et biophysica acta. Biomembranes · 2018Article
- Conformational Landscape of the PRKACA-DNAJB1 Chimeric Kinase, the Driver for Fibrolamellar Hepatocellular Carcinoma.Scientific reports · 2018Article
- Binding mechanism and dynamic conformational change of C subunit of PKA with different pathways.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Altering the allosteric pathway in IGPS suppresses millisecond motions and catalytic activity.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia.The Journal of biological chemistry · 2017Article
- A dynamic hydrophobic core orchestrates allostery in protein kinases.Science advances · 2017Article
- Uncoupling Catalytic and Binding Functions in the Cyclic AMP-Dependent Protein Kinase A.Structure (London, England : 1993) · 2016Article
- Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG).The Journal of biological chemistry · 2015Article
- Dynamics-Driven Allostery in Protein Kinases.Trends in biochemical sciences · 2015Review
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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 levels for proper Ca(2+) signaling and normal cardiac function.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.