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Cardiac myosin binding protein-C: redefining its structure and function

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Abstract

Mutations of cardiac myosin binding protein-C (cMyBP-C) are inherited by an estimated 60 million people worldwide, and the protein is the target of several kinases. Recent evidence further suggests that cMyBP-C mutations alter Ca2+ transients, leading to electrophysiological dysfunction. Thus, while the importance of studying this cardiac sarcomere protein is clear, preliminary data in the literature have raised many questions. Therefore, in this article, we propose to review the structure and function of cMyBP-C with particular respect to the role(s) in cardiac contractility and whether its release into the circulatory system is a potential biomarker of myocardial infarction. We also discuss future directions and experimental designs that may lead to expanding the role(s) of cMyBP-C in the heart. In conclusion, we suggest that cMyBP-C is a regulatory protein that could offer a broad clinical utility in maintaining normal cardiac function.

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Abbreviations

α-TM:

α-tropomyosin

cTnI:

Cardiac troponin I

cTnT:

Cardiac troponin T

cMyBP-C:

Cardiac myosin binding protein-C

DCM:

Dilated cardiomyopathy

HCM:

Hypertrophic cardiomyopathy

HF:

Heart failure

kDa:

Kilo Dalton

LV:

Left ventricular

MI:

Myocardial infarction

References

  • Ababou A, Gautel M, Pfuhl M (2007) Dissecting the N-terminal myosin binding site of human cardiac myosin-binding protein C. Structure and myosin binding of domain C2. J Biol Chem 282(12):9204–9215

    Google Scholar 

  • Ababou A, Rostkova E, Mistry S, Le Masurier C, Gautel M, Pfuhl M (2008) Myosin binding protein C positioned to play a key role in regulation of muscle contraction: structure and interactions of domain C1.J Mol Biol 384:615–630

    Google Scholar 

  • Ackermann MA, Kontrogianni-Konstantopoulos A (2011a) Myosin binding protein-C slow is a novel substrate for protein kinase A (PKA) and C (PKC) in skeletal muscle. J Proteome Res 10:4547–4555

    Article  PubMed  CAS  Google Scholar 

  • Ackermann MA, Kontrogianni-Konstantopoulos A (2011b) Myosin binding protein-C: a regulator of actomyosin interaction in striated muscle. J Biomed Biotechnol. doi:10.1155/2011/636403

  • Ahmad F, Banerjee SK, Lage ML, Huang XN, Smith SH, Saba S, Rager J, Conner DA, Janczewski AM, Tobita K, Tinney JP, Moskowitz IP, Perez-Atayde AR, Keller BB, Mathier MA, Shroff SG, Seidman CE, Seidman JG (2008) The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy. PLoS One 3:e2642

    Article  PubMed  CAS  Google Scholar 

  • Bahler M, Moser H, Eppenberger HM, Wallimann T (1985) Heart C-protein is transiently expressed during skeletal muscle development in the embryo, but persists in cultured myogenic cells. Dev Biol 112:345–352

    Article  PubMed  CAS  Google Scholar 

  • Bahrudin U, Morisaki H, Morisaki T, Ninomiya H, Higaki K, Nanba E, Igawa O, Takashima S, Mizuta E, Miake J, Yamamoto Y, Shirayoshi Y, Kitakaze M, Carrier L, Hisatome I (2008) Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy. J Mol Biol 384:896–907

    Article  PubMed  CAS  Google Scholar 

  • Bahrudin U, Morikawa K, Takeuchi A, Kurata Y, Miake J, Mizuta E, Adachi K, Higaki K, Yamamoto Y, Shirayoshi Y, Yoshida A, Kato M, Yamamoto K, Nanba E, Morisaki H, Morisaki T, Matsuoka S, Ninomiya H, Hisatome I (2011) Impairment of Ubiquitin-Proteasome System by E334K cMyBPC Modifies Channel Proteins, Leading to Electrophysiological Dysfunction. J Mol Biol 413:857–878

    Article  PubMed  CAS  Google Scholar 

  • Baker JO, Devaraj R, Reinhold J, Kanaganayagam GS, Sadayappan S, Gautel M, Redwood C, Marber M (2010) Cardiac myosin binding protein-C (cMyBP-C) as a potential new serum biomarker of myocardial infarction. Circulation 122:A15438

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bardswell SC, Cuello F, Kentish JC, Avkiran M (2011) cMyBP-C as a promiscuous substrate: phosphorylation by non-PKA kinases and its potential significance. J Muscle Res Cell Motil. doi:10.1007/s10974-10011-19276-10973

  • Barefield D, Sadayappan S (2010) Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol 48:866–875

    Article  PubMed  CAS  Google Scholar 

  • Berul CI, McConnell BK, Wakimoto H, Moskowitz IP, Maguire CT, Semsarian C, Vargas MM, Gehrmann J, Seidman CE, Seidman JG (2001) Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant Myosin-binding protein C gene. Circulation 104:2734–2739

    Article  PubMed  CAS  Google Scholar 

  • Bonne G, Carrier L, Richard P, Hainque B, Schwartz K (1998) Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res 83:580–593

    PubMed  CAS  Google Scholar 

  • Brickson S, Fitzsimons DP, Pereira L, Hacker T, Valdivia H, Moss RL (2007) In vivo left ventricular functional capacity is compromised in cMyBP-C null mice. Am J Physiol Heart Circ Physiol 292:H1747–H1754

    Article  PubMed  CAS  Google Scholar 

  • Carrier L, Bonne G, Bahrend E, Yu B, Richard P, Niel F, Hainque B, Cruaud C, Gary F, Labeit S, Bouhour JB, Dubourg O, Desnos M, Hagege AA, Trent RJ, Komajda M, Fiszman M, Schwartz K (1997) Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res 80:427–434

    PubMed  CAS  Google Scholar 

  • Carrier L, Knoll R, Vignier N, Keller DI, Bausero P, Prudhon B, Isnard R, Ambroisine ML, Fiszman M, Ross J Jr, Schwartz K, Chien KR (2004) Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice. Cardiovasc Res 63:293–304

    Article  PubMed  CAS  Google Scholar 

  • Carrier L, Schlossarek S, Willis MS, Eschenhagen T (2010) The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy. Cardiovasc Res 85:330–338

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, Qing Q, Ding G, Huang Y, Floyd D, Woods D, Yang Q (2003) Substitution of a constantly phosphorylated cardiac myosin binding protein C in transgenic mouse hearts enhances cardiac performance. Circulation Suppl IV 108:IV-90

    Google Scholar 

  • Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, Tsyrlin VA, Greenberg BH, Mayet J, Francis DP, Shaburishvili T, Monaghan M, Saltzberg M, Neyses L, Wasserman SM, Lee JH, Saikali KG, Clarke CP, Goldman JH, Wolff AA, Malik FI (2011) The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378:676–683

    Article  PubMed  CAS  Google Scholar 

  • Colson BA, Bekyarova T, Fitzsimons DP, Irving TC, Moss RL (2007) Radial displacement of myosin cross-bridges in mouse myocardium due to ablation of myosin binding protein-C. J Mol Biol 367:36–41

    Article  PubMed  CAS  Google Scholar 

  • Colson BA, Bekyarova T, Locher MR, Fitzsimons DP, Irving TC, Moss RL (2008) Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium. Circ Res 103:244–251

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • de Tombe PP, Mateja RD, Kittipong T, Mou YA, Farman GP, Irving TC (2010) Myofilament length dependent activation. J Mol Cell Cardiol 48:851–858

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards MB, Price AL, Patterson N, Reich D, Singh L, Tyler-Smith C, Thangaraj K (2009) A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 41:187–191

    Article  PubMed  CAS  Google Scholar 

  • Einheber S, Fischman DA (1990) Isolation and characterization of a cDNA clone encoding avian skeletal muscle C-protein: an intracellular member of the immunoglobulin superfamily. Proc Natl Acad Sci USA 87:2157–2161

    Article  PubMed  CAS  Google Scholar 

  • El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D (2006) Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 114:670–680

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • England PJ, Jeacocke SA, Huggins JP, Mills D, Pask HT (1983) Protein phosphorylation in the regulation of cardiac contraction. Biochem Soc Trans 11 Pt 2:153

    Google Scholar 

  • Eppenberger HM, Perriard JC, Rosenberg UB, Strehler EE (1981) The Mr 165,000 M-protein myomesin: a specific protein of cross-striated muscle cells. J Cell Biol 89:185–193

    Article  PubMed  CAS  Google Scholar 

  • Farman GP, Allen EJ, Schoenfelt KQ, Backx PH, de Tombe PP (2010) The role of thin filament cooperativity in cardiac length-dependent calcium activation. Biophys J 99:2978–2986

    Article  PubMed  CAS  Google Scholar 

  • Farman GP, Gore D, Allen E, Schoenfelt K, Irving TC, de Tombe PP (2011) Myosin head orientation: a structural determinant for the Frank-Starling relationship. Am J Physiol Heart Circ Physiol 300:H2155–H2160

    Article  PubMed  CAS  Google Scholar 

  • Flashman E, Redwood C, Moolman-Smook J, Watkins H (2004) Cardiac myosin binding protein C: its role in physiology and disease. Circ Res 94:1279–1289

    Article  PubMed  CAS  Google Scholar 

  • Flashman E, Korkie L, Watkins H, Redwood C, Moolman-Smook JC (2008) Support for a trimeric collar of myosin binding protein C in cardiac and fast skeletal muscle, but not in slow skeletal muscle. FEBS Lett 582:434–438

    Article  PubMed  CAS  Google Scholar 

  • Freiburg A, Gautel M (1996)A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy.Eur J Biochem 235:317–323

    Google Scholar 

  • Furst DO, Vinkemeier U, Weber K (1992) Mammalian skeletal muscle C-protein: purification from bovine muscle, binding to titin and the characterization of a full-length human cDNA. J Cell Sci 102:769–778

    PubMed  Google Scholar 

  • Gao WD, Perez NG, Seidman CE, Seidman JG, Marban E (1999) Altered cardiac excitation-contraction coupling in mutant mice with familial hypertrophic cardiomyopathy. J Clin Invest 103:661–666

    Article  PubMed  CAS  Google Scholar 

  • Garvey JL, Kranias EG, Solaro RJ (1988) Phosphorylation of C-protein, troponin I and phospholamban in isolated rabbit hearts. Biochem J 249:709–714

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Govindan S, McElligott A, Muthusamy S, Nair N, Barefield D, Greis KD, Martin JL, Gongora E, Luther PK, Winegrad S, Henderson KK, Sadayappan S (2012) Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction. J Mol Cell Cardiol 52:154–164

    Article  PubMed  CAS  Google Scholar 

  • Gruen M, Gautel M (1999) Mutations in beta-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C..J Mol Biol 286:933–949

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Guinto PJ, Haim TE, Dowell-Martino CC, Sibinga N, Tardiff JC (2009) Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models. Am J Physiol Heart Circ Physiol 297:H614–H626

    Article  PubMed  CAS  Google Scholar 

  • Harpaz Y, Chothia C (1994) Many of the immunoglobulin superfamily domains in cell adhesion molecules and surface receptors belong to a new structural set which is close to that containing variable domains. J Mol Biol 238:528–539

    Article  PubMed  CAS  Google Scholar 

  • Harris SP, Bartley CR, Hacker TA, McDonald KS, Douglas PS, Greaser ML, Powers PA, Moss RL (2002) Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res 90:594–601

    Article  PubMed  CAS  Google Scholar 

  • Harris SP, Rostkova E, Gautel M, Moss RL (2004) Binding of myosin binding protein-C to myosin subfragment S2 affects contractility independent of a tether mechanism. Circ Res 95:930–936

    Article  PubMed  CAS  Google Scholar 

  • Harris SP, Lyons RG, Bezold KL (2011) In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament. Circ Res 108:751–764

    Article  PubMed  CAS  Google Scholar 

  • Howarth JW, Ramisetti S, Nolan K, Sadayappan S, Rosevear PR (2012) Structural Insight into the unique cardiac myosin binding protein-C motif: a partially folded domain. J Biol Chem. doi:10.1074/jbc.M1111.309591

  • Huang X, Pi Y, Lee KJ, Henkel AS, Gregg RG, Powers PA, Walker JW (1999) Cardiac troponin I gene knockout: a mouse model of myocardial troponin I deficiency. Circ Res 84:1–8

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • James J, Robbins J (2011) Signaling and myosin-binding protein C. J Biol Chem 286:9913–9919

    Article  PubMed  CAS  Google Scholar 

  • Jeacocke SA, England PJ (1980) Phosphorylation of a myofibrillar protein of Mr 150 000 in perfused rat heart, and the tentative indentification of this as C-protein. FEBS Lett 122:129–132

    Article  PubMed  CAS  Google Scholar 

  • Jeffries CM, Whitten AE, Harris SP, Trewhella J (2008) Small-angle X-ray scattering reveals the N-terminal domain organization of cardiac myosin binding protein C. J Mol Biol 377:1186–1199

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jones WK, Grupp IL, Doetschman T, Grupp G, Osinska H, Hewett TE, Boivin G, Gulick J, Ng WA, Robbins J (1996) Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. J Clin Invest 98:1906–1917

    Article  PubMed  CAS  Google Scholar 

  • Karsai A, Kellermayer MS, Harris SP (2011) Mechanical unfolding of cardiac Myosin binding protein-C by atomic force microscopy. Biophys J 101:1968–1977

    Article  PubMed  CAS  Google Scholar 

  • Kawashima M, Kitani S, Tanaka T, Obinata T (1986) The earliest form of C-protein expressed during striated muscle development is immunologically the same as cardiac-type C-protein. J Biochem 99:1037–1047

    PubMed  CAS  Google Scholar 

  • Kensler RW, Shaffer JF, Harris SP (2011) Binding of the N-terminal fragment C0-C2 of cardiac MyBP-C to cardiac F-actin. J Struct Biol 174:44–51

    Article  PubMed  CAS  Google Scholar 

  • Koretz JF, Irving TC, Wang K (1993) Filamentous aggregates of native titin and binding of C-protein and AMP-deaminase. Arch Biochem Biophys 304:305–309

    Article  PubMed  CAS  Google Scholar 

  • Kulikovskaya I, McClellan G, Flavigny J, Carrier L, Winegrad S (2003) Effect of MyBP-C binding to actin on contractility in heart muscle. J Gen Physiol 122:761–774

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Crawford K, Close L, Madison M, Lorenz J, Doetschman T, Pawlowski S, Duffy J, Neumann J, Robbins J, Boivin GP, O'Toole BA, Lessard JL (1997) Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin. Proc Natl Acad Sci USA 94:4406–4411

    Article  PubMed  CAS  Google Scholar 

  • Kunst G, Kress KR, Gruen M, Uttenweiler D, Gautel M, Fink RH (2000) Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2. Circ Res 86:51–58

    PubMed  CAS  Google Scholar 

  • Labeit S, Gautel M, Lakey A, Trinick J (1992) Towards a molecular understanding of titin. EMBO J 11:1711–1716

    PubMed  CAS  Google Scholar 

  • Lakey A, Labeit S, Gautel M, Ferguson C, Barlow DP, Leonard K, Bullard B (1993) Kettin, a large modular protein in the Z-disc of insect muscles. EMBO J 12:2863–2871

    PubMed  CAS  Google Scholar 

  • Lim MS, Sutherland C, Walsh MP (1985) Phosphorylation of bovine cardiac C-protein by protein kinase C. Biochem Biophys Res Commun 132:1187–1195

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Kwan AH, Trewhella J, Jeffries CM (2011) The C0C1 Fragment of human cardiac myosin binding protein C has common binding determinants for both actin and myosin. J Mol Biol 413:908–913

    Article  PubMed  CAS  Google Scholar 

  • Luther PK, Bennett PM, Knupp C, Craig R, Padron R, Harris SP, Patel J, Moss RL (2008) Understanding the organisation and role of myosin binding protein C in normal striated muscle by comparison with MyBP-C knockout cardiac muscle. J Mol Biol 384:60–72

    Article  PubMed  CAS  Google Scholar 

  • Luther PK, Winkler H, Taylor K, Zoghbi ME, Craig R, Padron R, Squire JM, Liu J (2011) Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle. Proc Natl Acad Sci USA 108:11423–11428

    Article  PubMed  CAS  Google Scholar 

  • Malik FI, Morgan BP (2011) Cardiac myosin activation part 1: from concept to clinic. J Mol Cell Cardiol 51:454–461

    Article  PubMed  CAS  Google Scholar 

  • Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W, Katori T, Kass DA, Shen YT, Vatner SF, Morgans DJ (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331:1439–1443

    Article  PubMed  CAS  Google Scholar 

  • Manning EP, Tardiff JC, Schwartz SD (2011) A model of calcium activation of the cardiac thin filament. Biochemistry 50:7405–7413

    Article  PubMed  CAS  Google Scholar 

  • Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE (2001) Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations.J Am Coll Cardiol: 38:315–321

    Google Scholar 

  • Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H (2009) Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res 105:219–222

    Article  PubMed  CAS  Google Scholar 

  • McClellan G, Kulikovskaya I, Winegrad S (2001) Changes in cardiac contractility related to calcium-mediated changes in phosphorylation of myosin-binding protein C. Biophys J 81:1083–1092

    Article  PubMed  CAS  Google Scholar 

  • 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, Fischman DH (1999) Dilated cardiomyopathy in homozygous myosin binding protein-C mutant mice. J Clin Invest 104:1235–1244

    Article  PubMed  CAS  Google Scholar 

  • McConnell BK, Fatkin D, Semsarian C, Jones KA, Georgakopoulos D, Maguire CT, Healey MJ, Mudd JO, Moskowitz IP, Conner DA, Giewat M, Wakimoto H, Berul CI, Schoen FJ, Kass DA, Seidman CE, Seidman JG (2001) Comparison of two murine models of familial hypertrophic cardiomyopathy. Circ Res 88:383–389

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Moolman JA, Reith S, Uhl K, Bailey S, Gautel M, Jeschke B, Fischer C, Ochs J, McKenna WJ, Klues H, Vosberg HP (2000) A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation 101:1396–1402

    PubMed  CAS  Google Scholar 

  • Moolman-Smook J, Flashman E, de Lange W, Li Z, Corfield V, Redwood C, Watkins H (2002) Identification of novel interactions between domains of Myosin binding protein-C that are modulated by hypertrophic cardiomyopathy missense mutations. Circ Res 91:704–711

    Article  PubMed  CAS  Google Scholar 

  • Moos C (1981) Fluorescence microscope study of the binding of added C protein to skeletal muscle myofibrils. J Cell Biol 90:25–31

    Article  PubMed  CAS  Google Scholar 

  • Moos C, Mason CM, Besterman JM, Feng IN, Dubin JH (1978) The binding of skeletal muscle C-protein to F-actin, and its relation to the interaction of actin with myosin subfragment-1. J Mol Biol 124:571–586

    Article  PubMed  CAS  Google Scholar 

  • Mun JY, Gulick J, Robbins J, Woodhead J, Lehman W, Craig R (2011) Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C). J Mol Biol 410:214–225

    Article  PubMed  CAS  Google Scholar 

  • Nagayama T, Takimoto E, Sadayappan S, Mudd JO, Seidman JG, Robbins J, Kass DA (2007) Control of in vivo left ventricular contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation 116:2399–2408

    Article  PubMed  CAS  Google Scholar 

  • Offer G, Moos C, Starr R (1973) A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization.J Mol Biol 74:653–676

    Google Scholar 

  • Orlova A, Galkin VE, Jeffries CM, Egelman EH, Trewhella J (2011) The N-terminal domains of myosin binding protein C can bind polymorphically to F-actin. J Mol Biol 412:379–386

    Article  PubMed  CAS  Google Scholar 

  • Palmer BM, McConnell BK, Li GH, Seidman CE, Seidman JG, Irving TC, Alpert NR, Maughan DW (2004) Reduced cross-bridge dependent stiffness of skinned myocardium from mice lacking cardiac myosin binding protein-C. Mol Cell Biochem 263:73–80

    Article  PubMed  CAS  Google Scholar 

  • Palmer BM, Sadayappan S, Wang Y, Weith AE, Previs MJ, Bekyarova T, Irving TC, Robbins J, Maughan DW (2011) Roles for Cardiac MyBP-C in Maintaining Myofilament Lattice Rigidity and Prolonging Myosin Cross-Bridge Lifetime. Biophys J 101:1661–1669

    Article  PubMed  CAS  Google Scholar 

  • Pohlmann L, Kroger I, Vignier N, Schlossarek S, Kramer E, Coirault C, Sultan KR, El-Armouche A, Winegrad S, Eschenhagen T, Carrier L (2007) Cardiac myosin-binding protein C is required for complete relaxation in intact myocytes. Circ Res 101:928–938

    Article  PubMed  CAS  Google Scholar 

  • Ratti J, Rostkova E, Gautel M, Pfuhl M (2011) Structure and interactions of myosin-binding protein C domain C0: cardiac-specific regulation of myosin at its neck?J Biol Chem 286:12650–12658

    Google Scholar 

  • Razumova MV, Shaffer JF, Tu AY, Flint GV, Regnier M, Harris SP (2006) Effects of the N-terminal domains of myosin binding protein-C in an in vitro motility assay: Evidence for long-lived cross-bridges. J Biol Chem 281:35846–35854

    Article  PubMed  CAS  Google Scholar 

  • Redwood CS, Moolman-Smook JC, Watkins H (1999) Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy. Cardiovasc Res 44:20–36

    Google Scholar 

  • Rethinasamy P, Muthuchamy M, Hewett T, Boivin G, Wolska BM, Evans C, Solaro RJ, Wieczorek DF (1998) Molecular and physiological effects of alpha-tropomyosin ablation in the mouse. Circ Res 82:116–123

    PubMed  CAS  Google Scholar 

  • Rottbauer W, Gautel M, Zehelein J, Labeit S, Franz WM, Fischer C, Vollrath B, Mall G, Dietz R, Kubler W, Katus HA (1997) Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization Of cardiac transcript and protein. J Clin Invest 100:475–482

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Saad AD, Obinata T, Fischman DA (1987) Immunochemical analysis of protein isoforms in thick myofilaments of regenerating skeletal muscle. Dev Biol 119:336–349

    Article  PubMed  CAS  Google Scholar 

  • Sadayappan S, Robbins J (2008) The death of transcriptional chauvinism in the control and regulation of cardiac contractility. Ann N Y Acad Sci 1123:1–9

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 103:16918–16923

    Article  PubMed  CAS  Google Scholar 

  • Sadayappan S, Greis K, Robbins J (2008) Phosphorylation-dependent proteolysis and pathogenesis of cardiac myosin binding protein–C. J Mol Cell Cardiol 44:S44

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Sanada S, Asanuma H, Tsukamoto O, Minamino T, Node K, Takashima S, Fukushima T, Ogai A, Shinozaki Y, Fujita M, Hirata A, Okuda H, Shimokawa H, Tomoike H, Hori M, Kitakaze M (2004) Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C. Circulation 110:51–57

    Article  PubMed  CAS  Google Scholar 

  • Sarikas A, Carrier L, Schenke C, Doll D, Flavigny J, Lindenberg KS, Eschenhagen T, Zolk O (2005) Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. Cardiovasc Res 66:33–44

    Article  PubMed  CAS  Google Scholar 

  • Schlender KK, Bean LJ (1991) Phosphorylation of chicken cardiac C-protein by calcium/calmodulin-dependent protein kinase II. J Biol Chem 266:2811–2817

    PubMed  CAS  Google Scholar 

  • Schlender KK, Hegazy MG, Thysseril TJ (1987) Dephosphorylation of cardiac myofibril C-protein by protein phosphatase 1 and protein phosphatase 2A. Biochim Biophys Acta 928:312–319

    Article  PubMed  CAS  Google Scholar 

  • Schlender KK, Thysseril TJ, Hegazy MG (1988) Calcium-dependent phosphorylation of bovine cardiac C-protein by phosphorylase kinase. Biochem Biophys Res Commun 155:45–51

    Article  PubMed  CAS  Google Scholar 

  • Schlossarek S, Carrier L (2011) The ubiquitin-proteasome system in cardiomyopathies. Curr Opin Cardiol 26:190–195

    Article  PubMed  Google Scholar 

  • Schlossarek S, Mearini G, Carrier L (2011a) Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities. J Mol Cell Cardiol 50:613–620

    Article  PubMed  CAS  Google Scholar 

  • Semsarian C, Seidman CE (2001) Molecular medicine in the 21st century.Intern Med J 31:53–59

    Google Scholar 

  • Schlossarek S, Schuermann F, Geertz B, Mearini G, Eschenhagen T, Carrier L (2011b) Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice. J Muscle Res Cell Motil. doi:10.1007/s10974-10011-19273-10976

  • Shaffer JF, Jia W,Leary JA,Harris SP (2009a)PKA phosphorylates serine 307 of murine cardiac myosin binding protein-C in vitro.Biophys J 96:500a

  • Shaffer JF, Kensler RW, Harris SP (2009b) The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J Biol Chem 284:12318–12327

    Article  PubMed  CAS  Google Scholar 

  • Shaffer JF, Wong P, Bezold KL, Harris SP (2010) Functional differences between the N-terminal domains of mouse and human myosin binding protein-C. J Biomed Biotechnol 2010:789798

    Article  PubMed  CAS  Google Scholar 

  • Squire JM, Luther PK, Knupp C (2003) Structural evidence for the interaction of C-protein (MyBP-C) with actin and sequence identification of a possible actin-binding domain. J Mol Biol 331:713–724

    Article  PubMed  CAS  Google Scholar 

  • Squire JM, Roessle M, Knupp C (2004) New X-ray diffraction observations on vertebrate muscle: organisation of C-protein (MyBP-C) and troponin and evidence for unknown structures in the vertebrate A-band. J Mol Biol 343:1345–1363

    Article  PubMed  CAS  Google Scholar 

  • Starr R, Offer G (1971) Polypeptide chains of intermediate molecular weight in myosin preparations. FEBS Lett 15:40–44

    Article  PubMed  CAS  Google Scholar 

  • Steiner F, Weber K, Furst DO (1998) Structure and expression of the gene encoding murine M-protein, a sarcomere-specific member of the immunoglobulin superfamily. Genomics 49:83–95

    Article  PubMed  CAS  Google Scholar 

  • Stelzer JE, Dunning SB, Moss RL (2006a) Ablation of cardiac myosin-binding protein-C accelerates stretch activation in murine skinned myocardium. Circ Res 98:1212–1218

    Article  PubMed  CAS  Google Scholar 

  • Stelzer JE, Fitzsimons DP, Moss RL (2006b) Ablation of myosin-binding protein-C accelerates force development in mouse myocardium. Biophys J 90:4119–4127

    Article  PubMed  CAS  Google Scholar 

  • Stelzer JE, Patel JR, Moss RL (2006c) 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

    Article  PubMed  CAS  Google Scholar 

  • Stelzer JE, Patel JR, Walker JW, Moss RL (2007) Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation. Circ Res 101:503–511

    Article  PubMed  CAS  Google Scholar 

  • Takai Y, Nakanishi H (2003) Nectin and afadin: novel organizers of intercellular junctions. J Cell Sci 116:17–27

    Article  PubMed  CAS  Google Scholar 

  • Talan MI, Ahmet I, Xiao RP, Lakatta EG (2011) beta AR agonists in treatment of chronic heart failure: long path to translation. J Mol Cell Cardiol 51:529–533

    Article  PubMed  CAS  Google Scholar 

  • Tardiff JC (2011) Thin filament mutations: developing an integrative approach to a complex disorder. Circ Res 108:765–782

    Article  PubMed  CAS  Google Scholar 

  • Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42:270–283

    Article  PubMed  CAS  Google Scholar 

  • Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL (2008) Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res 103:974–982

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Vaughan KT, Weber FE, Fischman DA (1992) cDNA cloning and sequence comparisons of human and chicken muscle C-protein and 86kD protein. Symp Soc Exp Biol 46:167–177

    PubMed  CAS  Google Scholar 

  • Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L (2009) Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice. Circ Res 105:239–248

    Article  PubMed  CAS  Google Scholar 

  • Waldmuller S, Sakthivel S, Saadi AV, Selignow C, Rakesh PG, Golubenko M, Joseph PK, Padmakumar R, Richard P, Schwartz K, Tharakan JM, Rajamanickam C, Vosberg HP (2003) Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 35:623–636

    Article  PubMed  CAS  Google Scholar 

  • Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG et al (1995) Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 332:1058–1064

    Article  PubMed  CAS  Google Scholar 

  • Weber FE, Vaughan KT, Reinach FC, Fischman DA (1993) Complete sequence of human fast-type and slow-type muscle myosin-binding-protein C (MyBP-C). Differential expression, conserved domain structure and chromosome assignment. Eur J Biochem 216:661–669

    Article  PubMed  CAS  Google Scholar 

  • Weisberg A, Winegrad S (1996) Alteration of myosin cross bridges by phosphorylation of myosin-binding protein C in cardiac muscle. Proc Natl Acad Sci USA 93:8999–9003

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Whitten AE, Jeffries CM, Harris SP, Trewhella J (2008) Cardiac myosin-binding protein C decorates F-actin: implications for cardiac function. Proc Natl Acad Sci USA 105:18360–18365

    Article  PubMed  CAS  Google Scholar 

  • Witt CC, Gerull B, Davies MJ, Centner T, Linke WA, Thierfelder L (2001) Hypercontractile properties of cardiac muscle fibers in a knock-in mouse model of cardiac myosin binding protein-C. J Biol Chem 276:5353–5359

    Article  PubMed  CAS  Google Scholar 

  • Xiao L, Zhao Q, Du Y, Yuan C, Solaro RJ, Buttrick PM (2007) PKCepsilon increases phosphorylation of the cardiac myosin binding protein C at serine 302 both in vitro and in vivo. Biochemistry 46:7054–7061

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto K (1986) The binding of skeletal muscle C-protein to regulated actin. FEBS Lett 208:123–127

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto K, Moos C (1983) The C-proteins of rabbit red, white, and cardiac muscles. J Biol Chem 258:8395–8401

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J (1999) In vivo modeling of myosin binding protein-C familial hypertrophic cardiomyopathy. Circ Res 85:841–847

    PubMed  CAS  Google Scholar 

  • Yang Q, Osinska H, Klevitsky R, Robbins J (2001) Phenotypic deficits in mice expressing a myosin binding protein-C lacking the titin and myosin binding domains. J Mol Cell Cardiol 33:1649–1658

    Article  PubMed  CAS  Google Scholar 

  • Yasuda M, Koshida S, Sato N, Obinata T (1995) Complete primary structure of chicken cardiac C-protein (MyBP-C) and its expression in developing striated muscles. J Mol Cell Cardiol 27:2275–2286

    Article  PubMed  CAS  Google Scholar 

  • Yoshikai S, Ikebe M (1992) Molecular cloning of the chicken gizzard telokin gene and cDNA. Arch Biochem Biophys 299:242–247

    Article  PubMed  CAS  Google Scholar 

  • Yuan C, Guo Y, Ravi R, Przyklenk K, Shilkofski N, Diez R, Cole RN, Murphy AM (2006) Myosin binding protein C is differentially phosphorylated upon myocardial stunning in canine and rat hearts– evidence for novel phosphorylation sites. Proteomics 6:4176–4186

    Article  PubMed  CAS  Google Scholar 

  • Zhao X, Ho D, Abarzua P, Dhar SK, Wang X, Jia Z, Pannirselvam M, Morgans DJ, Malik FI, Vatner SF (2011) Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension. J Pharmacol Exp Ther 339:307–312

    Article  PubMed  CAS  Google Scholar 

  • Zoghbi ME, Woodhead JL, Moss RL, Craig R (2008) Three-dimensional structure of vertebrate cardiac muscle myosin filaments.Proc Natl Acad Sci USA 105:2386–2390

    Google Scholar 

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Acknowledgments

This study was funded by National Institutes of Health grants R01HL105826 (Dr. Sadayappan) and HL101297, HL62426, and HL75494 (Dr. de Tombe) and American Heart Association - Scientist Development Grant (0830311 N to Dr. Sadayappan).

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  1. Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Ave., Maywood, IL, 60153, USA

    Sakthivel Sadayappan & Pieter P. de Tombe

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  1. Sakthivel Sadayappan
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  2. Pieter P. de Tombe
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Correspondence to Sakthivel Sadayappan.

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Sadayappan, S., de Tombe, P.P. Cardiac myosin binding protein-C: redefining its structure and function. Biophys Rev 4, 93–106 (2012). https://doi.org/10.1007/s12551-012-0067-x

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