Myosin binding protein-C phosphorylation is the principal mediator of protein kinase A effects on thick filament structure in myocardium

Brett A. Colson, Jitandrakumar R. Patel, Peter P. Chen, Tanya Bekyarova, Mohamed I. Abdalla, Carl W. Tong, Daniel P. Fitzsimons, Thomas C. Irving, Richard L. Moss

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a regulator of pump function in healthy hearts. However, the mechanisms of regulation by cAMP-dependent protein kinase (PKA)-mediated cMyBP-C phosphorylation have not been completely dissociated from other myofilament substrates for PKA, especially cardiac troponin I (cTnI). We have used synchrotron X-ray diffraction in skinned trabeculae to elucidate the roles of cMyBP-C and cTnI phosphorylation in myocardial inotropy and lusitropy. Myocardium in this study was isolated from four transgenic mouse lines in which the phosphorylation state of either cMyBP-C or cTnI was constitutively altered by site-specific mutagenesis. Analysis of peak intensities in X-ray diffraction patterns from trabeculae showed that cross-bridges are displaced similarly from the thick filament and toward actin (1) when both cMyBP-C and cTnI are phosphorylated, (2) when only cMyBP-C is phosphorylated, and (3) when cMyBP-C phosphorylation is mimicked by replacement with negative charge in its PKA sites. These findings suggest that phosphorylation of cMyBP-C relieves a constraint on cross-bridges, thereby increasing the proximity of myosin to binding sites on actin. Measurements of Ca2+-activated force in myocardium defined distinct molecular effects due to phosphorylation of cMyBP-C or co-phosphorylation with cTnI. Echocardiography revealed that mimicking the charge of cMyBP-C phosphorylation protects hearts from hypertrophy and systolic dysfunction that develops with constitutive dephosphorylation or genetic ablation, underscoring the importance of cMyBP-C phosphorylation for proper pump function.

Original languageEnglish (US)
Pages (from-to)609-616
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Issue number5
StatePublished - Nov 2012


  • Cross-bridge cycling kinetics
  • Low-angle X-ray diffraction
  • Myosin binding protein C
  • Phosphorylation
  • Protein kinase A
  • Troponin I

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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