Abstract
Cardiac myosin binding protein C (cMyBP-C) is an integral sarcomeric protein that associates with the thick, thin, and titin filament systems in the contractile apparatus. Three different isoforms of MyBP-C exist in mammalian muscle: slow skeletal (MyBPC1), fast skeletal (MyBP-C2, with several variants), and cardiac (cMyBP-C). Genetic screening studies show that mutations in MYBPC3 occur frequently and are responsible for as many as 30–35 % of identified cases of familial hypertrophic cardiomyopathy. The function of cMyBP-C is stringently regulated by its post-translational modification. In particular, the addition of phosphate groups occurs with high frequency on certain serine residues that are located in the cardiac-specific regulatory M domain. Phosphorylation of this domain has been extensively studied in vitro and in vivo. Phosphorylation of the M domain can regulate the manner in which actin and myosin interact, affecting the cross bridge cycle and ultimately, cardiac hemodynamics.
Similar content being viewed by others
References
Bardswell SC, Cuello F, Rowland AJ, Sadayappan S, Robbins J, Gautel M, Walker JW, Kentish JC, Avkiran M (2010) Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and cross-bridge cycling. J Biol Chem 285:5674–5682. doi:10.1074/jbc.M109.066456
Bhuiyan MS, Gulick J, Osinska H, Gupta M, Robbins J (2012) Determination of the critical residues responsible for cardiac myosin binding protein C's interactions. J Mol Cell Cardiol 53:838–847. doi:10.1016/j.yjmcc.2012.08.028
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840. doi:10.1126/Science.1175371
Copeland O, Sadayappan S, Messer AE, Steinen GJ, van der Velden J, Marston SB (2010) Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. J Mol Cell Cardiol 49:1003–1011. doi:10.1016/j.yjmcc.2010.09.007
Cuello F, Bardswell SC, Haworth RS, Ehler E, Sadayappan S, Kentish JC, Avkiran M (2011) Novel role for p90 ribosomal S6 kinase in the regulation of cardiac myofilament phosphorylation. J Biol Chem 286:5300–5310. doi:10.1074/jbc.M110.202713
Decker RS, Decker ML, Kulikovskaya I, Nakamura S, Lee DC, Harris K, Klocke FJ, Winegrad S (2005) Myosin-binding protein C phosphorylation, myofibril structure, and contractile function during low-flow ischemia. Circulation 111:906–912. doi:10.1161/01.CIR.0000155609.95618.75
Decker RS, Nakamura S, Decker ML, Sausamuta M, Sinno S, Harris K, Klocke FJ, Kulikovskaya I, Winegrad S (2012) The dynamic role of cardiac myosin binding protein-C during ischemia. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2012.01.006
El-Armouche A, Pohlmann L, Schlossarek S, Starbatty J, Yeh YH, Nattel S, Dobrev D, Eschenhagen T, Carrier L (2007) Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure. J Mol Cell Cardiol 43:223–229. doi:10.1016/j.yjmcc.2007.05.003
Flotho A, Melchior F (2013) Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 82:357–385. doi:10.1146/annurev-biochem-061909-093311
Gautel M, Zuffardi O, Freiburg A, Labeit S (1995) Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? EMBO J 14:1952–1960
Govindan S, Sarkey J, Ji X, Sundaresan NR, Gupta MP, de Tombe PP, Sadayappan S (2012) Pathogenic properties of the N-terminal region of cardiac myosin binding protein-C in vitro. J Muscle Res Cell Motil 33:17–30. doi:10.1007/s10974-012-9292-y
Gruen M, Prinz H, Gautel M (1999) cAPK-phosphorylation controls the interaction of the regulatory domain of cardiac myosin binding protein C with myosin-S2 in an on-off fashion. FEBS Lett 453:254–259
Gupta MK, Gulick J, James J, Osinska H, Lorenz JN, Robbins J Functional dissection of myosin binding protein C phosphorylation. J Mol Cell Cardiol. 64C:39–50 doi:http://dx.doi.org/10.1016/j.yjmcc.2013.08.006
Hartzell HC (1984) Phosphorylation of C-protein in intact amphibian cardiac muscle. Correlation between 32P incorporation and twitch relaxation. J Gen Physiol 83:563–588
Hynes NE, Ingham PW, Lim WA, Marshall CJ, Massague J, Pawson T (2013) Signalling change: signal transduction through the decades. Nat Rev Mol Cell Biol 14:393–398. doi:10.1038/nrm3581
Jacques AM, Copeland O, Messer AE, Gallon CE, King K, McKenna WJ, Tsang VT, Marston SB (2008) Myosin binding protein C phosphorylation in normal, hypertrophic and failing human heart muscle. J Mol Cell Cardiol 45:209–216. doi:10.1016/j.yjmcc.2008.05.020
Jia W, Shaffer JF, Harris SP, Leary JA (2010) Identification of novel protein kinase A phosphorylation sites in the M-domain of human and murine cardiac myosin binding protein-C using mass spectrometry analysis. J Proteome Res 9:1843–1853. doi:10.1021/pr901006h
Kooij V, Boontje N, Zaremba R, Jaquet K, dos Remedios C, Stienen GJ, van der Velden J (2010) Protein kinase C alpha and epsilon phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium. Basic Res Cardiol 105:289–300. doi:10.1007/s00395-009-0053-z
Kooij V, Holewinski RJ, Murphy AM, Van Eyk JE (2013) Characterization of the cardiac myosin binding protein-C phosphoproteome in healthy and failing human hearts. J Mol Cell Cardiol 60:116–120. doi:10.1016/j.yjmcc.2013.04.012
Kuster DW, Sequeira V, Najafi A, Boontje NM, Wijnker PJ, Witjas-Paalberends ER, Marston SB, Dos Remedios CG, Carrier L, Demmers JA, Redwood C, Sadayappan S, van der Velden J (2013) GSK3beta phosphorylates newly identified site in the proline-alanine-rich region of cardiac myosin-binding protein C and alters cross-bridge cycling kinetics in human: short communication. Circ Res 112:633–639. doi:10.1161/circresaha.112.275602
Lothrop AP, Torres MP, Fuchs SM (2013) Deciphering post-translational modification codes. FEBS Lett 587:1247–1257. doi:10.1016/j.febslet.2013.01.047
McConnell BK, Jones KA, Fatkin D, Arroyo LH, Lee RT, Aristizabal O, Turnbull DH, Georgakopoulos D, Kass D, Bond M, Niimura H, Schoen FJ, Conner D, Fischman DA, Seidman CE, Seidman JG (1999) Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Invest 104:1771
Mohamed AS, Dignam JD, Schlender KK (1998) Cardiac myosin-binding protein C (MyBP-C): identification of protein kinase A and protein kinase C phosphorylation sites. Arch Biochem Biophys 358:313–319. doi:10.1006/abbi.1998.0857
Nagayama T, Takimoto E, Sadayappan S, Mudd JO, Seidman JG, Robbins J, Kass DA (2007) Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation 116:2399–2408. doi:10.1161/CIRCULATIONAHA.107.706523
Previs MJ, Beck Previs S, Gulick J, Robbins J, Warshaw DM (2012) Molecular mechanics of cardiac myosin-binding protein C in native thick filaments. Science 337:1215–1218. doi:10.1126/science.1223602
Rybakova IN, Greaser ML, Moss RL (2011) Myosin binding protein C interaction with actin: characterization and mapping of the binding site. J Biol Chem 286:2008–2016. doi:10.1074/jbc.M110.170605
Sadayappan S, Gulick J, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Robbins J (2009) Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation 119:1253–1262. doi:10.1161/CIRCULATIONAHA.108.798983
Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J (2011) A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res 109:141–150. doi:10.1161/CIRCRESAHA.111.242560
Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW 2nd, Klevitsky R, Seidman CE, Seidman JG, Robbins J (2005) Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res 97:1156–1163. doi:10.1161/01.RES.0000190605.79013.4d
Sadayappan S, Osinska H, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Seidman CE, Seidman JG, Robbins J (2006) Cardiac myosin binding protein C phosphorylation is cardioprotective. Proc Natl Acad Sci U S A 103:16918–16923. doi:10.1073/Pnas.0607069103
Solaro RJ, Henze M, Kobayashi T (2013) Integration of troponin I phosphorylation with cardiac regulatory networks. Circ Res 112:355–366. doi:10.1161/circresaha.112.268672
Solaro RJ, Kobayashi T (2011) Protein phosphorylation and signal transduction in cardiac thin filaments. J Biol Chem 286:9935–9940. doi:10.1074/jbc.R110.197731
Stelzer JE, Dunning SB, Moss RL (2006) Ablation of cardiac myosin-binding protein-C accelerates stretch activation in murine skinned myocardium. Circ Res 98:1212–1218. doi:10.1161/01.RES.0000219863.94390.ce
Stelzer JE, Patel JR, Moss RL (2006) Protein kinase A-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cMyBP-C. Circ Res 99:884–890. doi:10.1161/01.RES.0000245191.34690.66
van Dijk SJ, Dooijes D, dos Remedios C, Michels M, Lamers JM, Winegrad S, Schlossarek S, Carrier L, ten Cate FJ, Stienen GJ, van der Velden J (2009) Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation 119:1473–1483. doi:10.1161/circulationaha.108.838672
Wachter SB, Gilbert EM (2012) Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology 122:104–112. doi:10.1159/000339271
Wang H, Grant JE, Doede CM, Sadayappan S, Robbins J, Walker JW (2006) PKC-betaII sensitizes cardiac myofilaments to Ca2+ by phosphorylating troponin I on threonine-144. J Mol Cell Cardiol 41:823–833. doi:10.1016/j.yjmcc.2006.08.016
Weith A, Sadayappan S, Gulick J, Previs MJ, Vanburen P, Robbins J, Warshaw DM (2012) Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain. J Mol Cell Cardiol 52:219–227. doi:10.1016/j.yjmcc.2011.09.019
Weith AE, Previs MJ, Hoeprich GJ, Previs SB, Gulick J, Robbins J, Warshaw DM (2012) The extent of cardiac myosin binding protein-C phosphorylation modulates actomyosin function in a graded manner. J Muscle Res Cell Motil 33(6):449–459. doi:10.1007/s10974-012-9312-y
Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J (1998) A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy. J Clin Invest 102:1292–1300. doi:10.1172/JCI3880
Acknowledgements
This work was supported by National Heart, Lung and Blood Institute grants P01HL077101, P01HL059408, and R01HL105924 and The Transatlantic Network of Excellence Program grant from Le Fondation Leducq (to J.R.). MKG is a post-doctoral fellow of American Heart Association (Great Rivers Affiliate).
Disclosures
None declared.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gupta, M.K., Robbins, J. Post-translational control of cardiac hemodynamics through myosin binding protein C. Pflugers Arch - Eur J Physiol 466, 231–236 (2014). https://doi.org/10.1007/s00424-013-1377-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-013-1377-y