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Regular Article

A Critical Function for Ser-282 in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function

Sakthivel Sadayappan, James Gulick, Hanna Osinska, David Barefield, Friederike Cuello, Metin Avkiran, Valerie M. Lasko, John N. Lorenz, Marjorie Maillet, Jody L. Martin, Joan Heller Brown, Donald M. Bers, Jeffery D. Molkentin, Jeanne James, Jeffrey Robbins
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https://doi.org/10.1161/CIRCRESAHA.111.242560
Circulation Research. 2011;CIRCRESAHA.111.242560
Originally published May 19, 2011
Sakthivel Sadayappan
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James Gulick
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Hanna Osinska
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David Barefield
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Friederike Cuello
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Metin Avkiran
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Valerie M. Lasko
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John N. Lorenz
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Marjorie Maillet
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Jody L. Martin
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Joan Heller Brown
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Donald M. Bers
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Jeffery D. Molkentin
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Jeanne James
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Jeffrey Robbins
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Abstract

Cardiac myosin-binding protein-C (cMyBP-C) phosphorylation at Ser-273, Ser-282, and Ser-302 regulates myocardial contractility. In vitro and in vivo experiments suggest the nonequivalence of these sites and the potential importance of Ser-282 phosphorylation in modulating the protein's overall phosphorylation and myocardial function. The objective was to determine whether complete cMyBP-C phosphorylation is dependent on Ser-282 phosphorylation and to define its role in myocardial function. We hypothesized that Ser-282 regulates Ser-302 phosphorylation and cardiac function during β-adrenergic stimulation. Using recombinant human C1-mol/L-C2 peptides in vitro, we determined that protein kinase A can phosphorylate Ser-273, Ser-282, and Ser-302. Protein kinase C can also phosphorylate Ser-273 and Ser-302. In contrast, Ca2+-calmodulin-activated kinase II targets Ser-302 but can also target Ser-282 at nonphysiological calcium concentrations. Strikingly, Ser-302 phosphorylation by Ca2+-calmodulin-activated kinase II was abolished by ablating the ability of Ser-282 to be phosphorylated via alanine substitution. To determine the functional roles of the sites in vivo, three transgenic lines, which expressed cMyBP-C containing either Ser-273-Ala-282-Ser-302 (cMyBP-CSAS), Ala-273-Asp-282-Ala-302 (cMyBP-CADA), or Asp-273-Ala-282-Asp-302 (cMyBP-CDAD), were generated. Mutant protein was completely substituted for endogenous cMyBP-C by breeding each mouse line into a cMyBP-C null (t/t) background. Serine-to-alanine substitutions were used to ablate the abilities of the residues to be phosphorylated, whereas serine-to-aspartate substitutions were used to mimic the charged state conferred by phosphorylation. Compared to control nontransgenic mice, as well as transgenic mice expressing wild-type cMyBP-C, the transgenic cMyBP-CSAS(t/t), cMyBP-CADA(t/t), and cMyBP-CDAD(t/t) mice showed no increases in morbidity and mortality and partially rescued the cMyBP-C(t/t) phenotype. The loss of cMyBP-C phosphorylation at Ser-282 led to an altered β-adrenergic response. In vivo hemodynamic studies revealed that contractility was unaffected but that cMyBP-CSAS(t/t) hearts showed decreased diastolic function at baseline. However, the normal increases in cardiac function (increased contractility/relaxation) as a result of infusion of β-agonist was significantly decreased in all of the mutants, suggesting that competency for phosphorylation at multiple sites in cMyBP-C is a prerequisite for normal β-adrenergic responsiveness. Ser-282 has a unique regulatory role in that its phosphorylation is critical for the subsequent phosphorylation of Ser-302. However, each residue plays a role in regulating the contractile response to β-agonist stimulation.

  • contractile function
  • myofilament
  • myosin-binding protein-C
  • phosphorylation
  • Received February 11, 2011.
  • Revision received May 5, 2011.
  • Accepted May 9, 2011.
  • © 2011 American Heart Association, Inc.
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    A Critical Function for Ser-282 in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function
    Sakthivel Sadayappan, James Gulick, Hanna Osinska, David Barefield, Friederike Cuello, Metin Avkiran, Valerie M. Lasko, John N. Lorenz, Marjorie Maillet, Jody L. Martin, Joan Heller Brown, Donald M. Bers, Jeffery D. Molkentin, Jeanne James and Jeffrey Robbins
    Circulation Research. 2011;CIRCRESAHA.111.242560, originally published May 19, 2011
    https://doi.org/10.1161/CIRCRESAHA.111.242560

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    A Critical Function for Ser-282 in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function
    Sakthivel Sadayappan, James Gulick, Hanna Osinska, David Barefield, Friederike Cuello, Metin Avkiran, Valerie M. Lasko, John N. Lorenz, Marjorie Maillet, Jody L. Martin, Joan Heller Brown, Donald M. Bers, Jeffery D. Molkentin, Jeanne James and Jeffrey Robbins
    Circulation Research. 2011;CIRCRESAHA.111.242560, originally published May 19, 2011
    https://doi.org/10.1161/CIRCRESAHA.111.242560
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