Cardiac myosin binding protein-C phosphorylation as a function of multiple 
protein kinase and phosphatase activities

Kampourakis, Thomas; Ponnam, Saraswathi; Campbell, Kenneth S.; Wellette-Hunsucker, Austin; Koch, Daniel

doi:10.1038/s41467-024-49408-5

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Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities

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Koch, Daniel
Lise Meitner Group Cellular Computations and Learning, Max Planck Institute for Neurobiology of Behavior – caesar, Max Planck Society;
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https://www.nature.com/articles/s41467-024-49408-5
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https://github.com/KochLabCode/cMyBP-C-phosphorylation
(Supplementary material)

https://zenodo.org/records/11308622
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Citation

Kampourakis, T., Ponnam, S., Campbell, K. S., Wellette-Hunsucker, A., & Koch, D. (2024). Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities. Nature Communications, 15: 5111. doi:10.1038/s41467-024-49408-5.

Cite as: https://hdl.handle.net/21.11116/0000-000F-6E76-2

Abstract

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a determinant of cardiac myofilament function. Although cMyBP-C phosphorylation by various protein kinases has been extensively studied, the influence of protein phosphatases on cMyBP-C’s multiple phosphorylation sites has remained largely obscure. Here we provide a detailed biochemical characterization of cMyBP-C dephosphorylation by protein phosphatases 1 and 2 A (PP1 and PP2A), and develop an integrated kinetic model for cMyBP-C phosphorylation using data for both PP1, PP2A and various protein kinases known to phosphorylate cMyBP-C. We find strong site-specificity and a hierarchical mechanism for both phosphatases, proceeding in the opposite direction of sequential phosphorylation by potein kinase A. The model is consistent with published data from human patients and predicts complex non-linear cMyBP-C phosphorylation patterns that are validated experimentally. Our results suggest non-redundant roles for PP1 and PP2A under both physiological and heart failure conditions, and emphasize the importance of phosphatases for cMyBP-C regulation.