Cardiac Myosin Binding Protein-C Phosphorylation As a Function of Multiple Protein Kinase and Phosphatase Activities

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jun 14

PMID 38877002

Authors

Thomas Kampourakis

Saraswathi Ponnam

Kenneth S Campbell

Austin Wellette-Hunsucker

Daniel Koch

Affiliations

Soon will be listed here.

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.

Citing Articles

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Gulbulak U, Wellette-Hunsucker A, Kampourakis T, Campbell K Am J Physiol Heart Circ Physiol. 2024; 327(3):H715-H721.

PMID: 39092999 PMC: 11427113. DOI: 10.1152/ajpheart.00144.2024.

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

Kampourakis T, Ponnam S, Campbell K, Wellette-Hunsucker A, Koch D Nat Commun. 2024; 15(1):5111.

PMID: 38877002 PMC: 11178824. DOI: 10.1038/s41467-024-49408-5.

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