Mybpc3

Summary

Gene Symbol: Mybpc3
Description: myosin binding protein C, cardiac
Alias: myosin-binding protein C, cardiac-type, C-protein, cardiac muscle isoform, cardiac C-protein, cardiac MyBP-C
Species: mouse
Products:     Mybpc3

Top Publications

  1. Stelzer J, Fitzsimons D, Moss R. Ablation of myosin-binding protein-C accelerates force development in mouse myocardium. Biophys J. 2006;90:4119-27 pubmed
    ..Together, these results support the idea that cMyBP-C normally acts to constrain the interaction between myosin and actin, which in turn limits steady-state force development and the kinetics of cross-bridge interaction. ..
  2. Carrier L, Knoll R, Vignier N, Keller D, Bausero P, Prudhon B, et al. Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice. Cardiovasc Res. 2004;63:293-304 pubmed
    ..These data provide evidence that heterozygous cMyBP-C null mice represent the first model with a key feature of human FHC that is asymmetric septal hypertrophy. ..
  3. Gautel M, Fürst D, Cocco A, Schiaffino S. Isoform transitions of the myosin binding protein C family in developing human and mouse muscles: lack of isoform transcomplementation in cardiac muscle. Circ Res. 1998;82:124-9 pubmed
    ..This suggests that transcomplementation of MyBP-C isoforms is possible in skeletal but not cardiac muscle. ..
  4. Wang L, Ji X, Barefield D, Sadayappan S, Kawai M. Phosphorylation of cMyBP-C affects contractile mechanisms in a site-specific manner. Biophys J. 2014;106:1112-22 pubmed publisher
    ..In contrast, a single change of residue 282 to nonphosphorylatable Ala (SAS), or to phosphomimetic Asps together with the changes of residues 273 and 302 to nonphosphorylatable Ala (ADA) causes minute changes in fiber mechanics. ..
  5. Colson B, Patel J, CHEN P, Bekyarova T, Abdalla M, Tong C, et al. Myosin binding protein-C phosphorylation is the principal mediator of protein kinase A effects on thick filament structure in myocardium. J Mol Cell Cardiol. 2012;53:609-16 pubmed publisher
  6. CHEN P, Patel J, Powers P, Fitzsimons D, Moss R. Dissociation of structural and functional phenotypes in cardiac myosin-binding protein C conditional knockout mice. Circulation. 2012;126:1194-205 pubmed publisher
  7. Fraysse B, Weinberger F, Bardswell S, Cuello F, Vignier N, Geertz B, et al. Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J Mol Cell Cardiol. 2012;52:1299-307 pubmed publisher
    Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C)...
  8. Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, et al. A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res. 2011;109:141-50 pubmed publisher
    ..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 ?-agonist stimulation. ..
  9. Colson B, Bekyarova T, Locher M, Fitzsimons D, Irving T, Moss R. Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium. Circ Res. 2008;103:244-51 pubmed publisher

More Information

Publications62

  1. Kensler R, Harris S. The structure of isolated cardiac Myosin thick filaments from cardiac Myosin binding protein-C knockout mice. Biophys J. 2008;94:1707-18 pubmed
    ..In addition, the cross-bridge array in the absence of cMyBP-C appears more easily disordered. ..
  2. Fougerousse F, Delezoide A, Fiszman M, Schwartz K, Beckmann J, Carrier L. Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development. Circ Res. 1998;82:130-3 pubmed
    ..Our results showed that during both human and murine development, in contrast to chicken development, the cardiac MyBP-C gene is abundantly and specifically expressed in the heart. ..
  3. Kurasawa M, Sato N, Matsuda A, Koshida S, Totsuka T, Obinata T. Differential expression of C-protein isoforms in developing and degenerating mouse striated muscles. Muscle Nerve. 1999;22:196-207 pubmed
    ..We also suggest that the expression of S isoform may be stimulated in degenerating human dystrophic muscles. ..
  4. McConnell B, Fatkin D, Semsarian C, Jones K, Georgakopoulos D, Maguire C, et al. Comparison of two murine models of familial hypertrophic cardiomyopathy. Circ Res. 2001;88:383-9 pubmed
    ..These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients. ..
  5. Harris S, Bartley C, Hacker T, McDonald K, Douglas P, Greaser M, et al. Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res. 2002;90:594-601 pubmed
    ..These results establish that cMyBP-C is not essential for cardiac development but that the absence of cMyBP-C results in profound cardiac hypertrophy and impaired contractile function. ..
  6. Brickson S, Fitzsimons D, Pereira L, Hacker T, Valdivia H, Moss R. In vivo left ventricular functional capacity is compromised in cMyBP-C null mice. Am J Physiol Heart Circ Physiol. 2007;292:H1747-54 pubmed
    ..These results suggest that the absence of cMyBP-C significantly diminishes in vivo LV function and markedly attenuates the increase in LV contractility following beta-adrenergic stimulation or adaptation to pressure overload. ..
  7. McConnell B, Jones K, Fatkin D, Arroyo L, Lee R, Aristizabal O, et al. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Invest. 1999;104:1235-44 pubmed
    ..We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans. ..
  8. Ababou A, Rostkova E, Mistry S, Le Masurier C, Gautel M, Pfuhl M. Myosin binding protein C positioned to play a key role in regulation of muscle contraction: structure and interactions of domain C1. J Mol Biol. 2008;384:615-30 pubmed publisher
    ..As a result, the myosin heads would always be attached to a tether that has phosphorylation-dependent length regulation. ..
  9. Shaffer J, Kensler R, Harris S. The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J Biol Chem. 2009;284:12318-27 pubmed publisher
    ..Reversible interactions with actin could contribute to effects of cMyBP-C to increase cross-bridge cycling. ..
  10. Nagayama T, Takimoto E, Sadayappan S, Mudd J, Seidman J, Robbins J, et al. Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation. 2007;116:2399-408 pubmed
    ..These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve. ..
  11. Mearini G, Gedicke C, Schlossarek S, Witt C, Kramer E, Cao P, et al. Atrogin-1 and MuRF1 regulate cardiac MyBP-C levels via different mechanisms. Cardiovasc Res. 2010;85:357-66 pubmed publisher
    ..These data suggest that atrogin-1 specifically targets truncated M7t-cMyBP-C, but not WT-cMyBP-C, for proteasomal degradation and that MuRF1 indirectly reduces cMyBP-C levels by regulating the transcription of MHC. ..
  12. Stelzer J, Patel J, Walker J, Moss R. Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation. Circ Res. 2007;101:503-11 pubmed
    ..These results predict that PKA phosphorylation of myofibrillar proteins in living myocardium contributes to accelerated relaxation in diastole and increased rates of force development in systole. ..
  13. Bardswell S, Cuello F, Rowland A, Sadayappan S, Robbins J, Gautel M, et al. Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and cross-bridge cycling. J Biol Chem. 2010;285:5674-82 pubmed publisher
    ..PKD phosphorylates cMyBP-C at Ser(302), which may mediate the latter effect. ..
  14. Colson B, Bekyarova T, Fitzsimons D, Irving T, Moss R. Radial displacement of myosin cross-bridges in mouse myocardium due to ablation of myosin binding protein-C. J Mol Biol. 2007;367:36-41 pubmed
  15. Stelzer J, Patel J, Moss R. Protein kinase A-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cMyBP-C. Circ Res. 2006;99:884-90 pubmed
  16. Janssen P. Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere. Am J Physiol Heart Circ Physiol. 2010;299:H1092-9 pubmed publisher
    ..85 ± 0.04). Because of the great variety in underlying excitation-contraction coupling in the assessed strains, we concluded that contraction-relation coupling is a property residing in the cardiac sarcomere. ..
  17. Cazorla O, Szilagyi S, Vignier N, Salazar G, Kramer E, Vassort G, et al. Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice. Cardiovasc Res. 2006;69:370-80 pubmed
  18. Schlossarek S, Schuermann F, Geertz B, Mearini G, Eschenhagen T, Carrier L. Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice. J Muscle Res Cell Motil. 2012;33:5-15 pubmed publisher
    ..cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C...
  19. Palmer B, Noguchi T, Wang Y, Heim J, Alpert N, Burgon P, et al. Effect of cardiac myosin binding protein-C on mechanoenergetics in mouse myocardium. Circ Res. 2004;94:1615-22 pubmed
  20. Palmer B, Georgakopoulos D, Janssen P, Wang Y, Alpert N, Belardi D, et al. Role of cardiac myosin binding protein C in sustaining left ventricular systolic stiffening. Circ Res. 2004;94:1249-55 pubmed
    ..Abnormal sarcomere shortening velocity and abbreviated muscle stiffening may underlie development of cardiac dysfunction associated with deficient incorporation of cMyBP-C. ..
  21. Yang Q, Sanbe A, Osinska H, Hewett T, Klevitsky R, Robbins J. A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy. J Clin Invest. 1998;102:1292-300 pubmed
    ..Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis. ..
  22. Luther P, Bennett P, Knupp C, Craig R, Padrón R, Harris S, et al. 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. 2008;384:60-72 pubmed publisher
    ..However, in the MyBP-C-deficient hearts these extra meridional reflections are weak or absent, suggesting that they are due to MyBP-C itself or to MyBP-C in combination with a head perturbation brought about by the presence of MyBP-C. ..
  23. Colson B, Rybakova I, Prochniewicz E, Moss R, Thomas D. Cardiac myosin binding protein-C restricts intrafilament torsional dynamics of actin in a phosphorylation-dependent manner. Proc Natl Acad Sci U S A. 2012;109:20437-42 pubmed publisher
    ..We propose that these MyBP-C-induced changes in actin dynamics play a role in the functional effects of MyBP-C on the actin-myosin interaction. ..
  24. Jeffries C, Whitten A, Harris S, Trewhella J. Small-angle X-ray scattering reveals the N-terminal domain organization of cardiac myosin binding protein C. J Mol Biol. 2008;377:1186-99 pubmed publisher
  25. Korte F, McDonald K, Harris S, Moss R. Loaded shortening, power output, and rate of force redevelopment are increased with knockout of cardiac myosin binding protein-C. Circ Res. 2003;93:752-8 pubmed
    ..8+/-0.9 s(-1) versus MyBP-C-/-=7.7+/-1.7 s(-1)). These results suggest that cMyBP-C is an important regulator of myocardial work capacity whereby MyBP-C acts to limit power output. ..
  26. Palmer B, McConnell B, Li G, Seidman C, Seidman J, Irving T, et al. Reduced cross-bridge dependent stiffness of skinned myocardium from mice lacking cardiac myosin binding protein-C. Mol Cell Biochem. 2004;263:73-80 pubmed
  27. Sadayappan S, Gulick J, Osinska H, Martin L, Hahn H, Dorn G, et al. Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res. 2005;97:1156-63 pubmed
    ..In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function. ..
  28. Tong C, Stelzer J, Greaser M, Powers P, Moss R. Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res. 2008;103:974-82 pubmed publisher
    ..Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction. ..
  29. Michalek A, Howarth J, Gulick J, Previs M, Robbins J, Rosevear P, et al. Phosphorylation modulates the mechanical stability of the cardiac myosin-binding protein C motif. Biophys J. 2013;104:442-52 pubmed publisher
    ..These biophysical data provide both a mechanical and structural basis for cMyBP-C regulation by motif phosphorylation. ..
  30. Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, et al. Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice. Circ Res. 2009;105:239-48 pubmed publisher
    Mutations in the MYBPC3 gene encoding cardiac myosin-binding protein (cMyBP)-C are frequent causes of hypertrophic cardiomyopathy, but the mechanisms leading from mutations to disease remain elusive...
  31. Pohlmann L, Kröger I, Vignier N, Schlossarek S, Kramer E, Coirault C, et al. Cardiac myosin-binding protein C is required for complete relaxation in intact myocytes. Circ Res. 2007;101:928-38 pubmed
    ..Our findings indicate that cMyBP-C functions as a restraint on myosin-actin interaction at low Ca2+ and short SL to allow complete relaxation during diastole. ..
  32. Stelzer J, Dunning S, Moss R. Ablation of cardiac myosin-binding protein-C accelerates stretch activation in murine skinned myocardium. Circ Res. 2006;98:1212-8 pubmed
  33. Zoghbi M, Woodhead J, Moss R, Craig R. Three-dimensional structure of vertebrate cardiac muscle myosin filaments. Proc Natl Acad Sci U S A. 2008;105:2386-90 pubmed publisher
    ..The techniques we have developed should be useful in studying the structural basis of other myosin-related HCM diseases. ..
  34. Palmer B, Sadayappan S, Wang Y, Weith A, Previs M, Bekyarova T, et al. Roles for cardiac MyBP-C in maintaining myofilament lattice rigidity and prolonging myosin cross-bridge lifetime. Biophys J. 2011;101:1661-9 pubmed publisher
    ..Although the presence of cMyBP-C also provides longitudinal rigidity, phosphorylation of the N-terminus is not necessary to maintain longitudinal rigidity of the lattice, in contrast to radial rigidity. ..
  35. Ackermann M, Hu L, Bowman A, Bloch R, Kontrogianni Konstantopoulos A. Obscurin interacts with a novel isoform of MyBP-C slow at the periphery of the sarcomeric M-band and regulates thick filament assembly. Mol Biol Cell. 2009;20:2963-78 pubmed publisher
    ..Collectively, our experiments identify a new ligand of obscurin at the M-band, MyBP-C slow variant-1 and suggest that their interaction contributes to the assembly of M- and A-bands. ..
  36. Harris S, Rostkova E, Gautel M, Moss R. Binding of myosin binding protein-C to myosin subfragment S2 affects contractility independent of a tether mechanism. Circ Res. 2004;95:930-6 pubmed
  37. Cheng Y, Wan X, McElfresh T, Chen X, Gresham K, Rosenbaum D, et al. Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere. Am J Physiol Heart Circ Physiol. 2013;305:H52-65 pubmed publisher
    ..Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia. ..
  38. Toib A, Zhang C, Borghetti G, Zhang X, Wallner M, Yang Y, et al. Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model. Am J Physiol Heart Circ Physiol. 2017;313:H620-H630 pubmed publisher
  39. Camacho P, Fan H, Liu Z, He J. Small mammalian animal models of heart disease. Am J Cardiovasc Dis. 2016;6:70-80 pubmed
  40. Taylor E, Hoffman M, Barefield D, Aninwene G, Abrishamchi A, Lynch T, et al. Alterations in Multi-Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein-C. J Am Heart Assoc. 2016;5:e002836 pubmed publisher
    ..Cardiac myosin binding protein-C (MYBPC3) is a sarcomeric protein, for which phosphorylation modulates myofilament binding, sarcomere morphology, and ..
  41. Kumar M, Govindan S, Zhang M, Khairallah R, Martin J, Sadayappan S, et al. Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation. J Biol Chem. 2015;290:29241-9 pubmed publisher
    ..We speculate that this molecular mechanism enhances cross-bridge formation at long SL while accelerating cross-bridge detachment and relaxation at short SLs. ..
  42. Jiang J, Burgon P, Wakimoto H, Onoue K, Gorham J, O Meara C, et al. Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis. Proc Natl Acad Sci U S A. 2015;112:9046-51 pubmed publisher
    ..Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation...
  43. Kasahara H, Itoh M, Sugiyama T, Kido N, Hayashi H, Saito H, et al. Autoimmune myocarditis induced in mice by cardiac C-protein. Cloning of complementary DNA encoding murine cardiac C-protein and partial characterization of the antigenic peptides. J Clin Invest. 1994;94:1026-36 pubmed
    ..This study provides a new animal model of autoimmune myocarditis which may shed light on the pathogenesis of dilated cardiomyopathy. ..
  44. Gedicke Hornung C, Behrens Gawlik V, Reischmann S, Geertz B, Stimpel D, Weinberger F, et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO Mol Med. 2013;5:1128-45 pubmed publisher
    ..We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM)...
  45. Sadayappan S, Gulick J, Klevitsky R, Lorenz J, Sargent M, Molkentin J, et al. Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation. 2009;119:1253-62 pubmed publisher
    ..Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart. ..
  46. Eijssen L, van den Bosch B, Vignier N, Lindsey P, van den Burg C, Carrier L, et al. Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice. Genomics. 2008;91:52-60 pubmed
    ..Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice. ..
  47. Rybakova I, Greaser M, Moss R. Myosin binding protein C interaction with actin: characterization and mapping of the binding site. J Biol Chem. 2011;286:2008-16 pubmed publisher
    ..In contrast, certain basic regions of the N-terminal domains of MyBPC may act as small polycations and therefore bind actin via nonspecific electrostatic interactions. ..
  48. Yang Q, Sanbe A, Osinska H, Hewett T, Klevitsky R, Robbins J. In vivo modeling of myosin binding protein C familial hypertrophic cardiomyopathy. Circ Res. 1999;85:841-7 pubmed
    ..Fiber mechanics showed decreased unloading shortening velocity, maximum shortening velocity, and relative maximal power output. ..
  49. Howarth J, Ramisetti S, Nolan K, Sadayappan S, Rosevear P. Structural insight into unique cardiac myosin-binding protein-C motif: a partially folded domain. J Biol Chem. 2012;287:8254-62 pubmed publisher
    ..Thus, the m-domain consists of an N-terminal subdomain that is flexible and largely disordered and a C-terminal subdomain having a three-helix bundle fold, potentially providing an actin-binding platform. ..
  50. Xiao L, Zhao Q, Du Y, Yuan C, Solaro R, Buttrick P. PKCepsilon increases phosphorylation of the cardiac myosin binding protein C at serine 302 both in vitro and in vivo. Biochemistry. 2007;46:7054-61 pubmed
    ..Taken together, our data show that the Ser302 on mouse cMyBPC is a likely PKCepsilon phosphorylation site both in vivo and in vitro and may contribute to the dilated cardiomyopathy associated with increased PKCepsilon activity. ..
  51. Song Q, Schmidt A, Hahn H, Carr A, Frank B, Pater L, et al. Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. J Clin Invest. 2003;111:859-67 pubmed
    ..Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations. ..
  52. Weith A, Previs M, Hoeprich G, Previs S, Gulick J, Robbins J, et al. The extent of cardiac myosin binding protein-C phosphorylation modulates actomyosin function in a graded manner. J Muscle Res Cell Motil. 2012;33:449-59 pubmed publisher
    ..This study suggests that increasing phosphorylation of cMyBP-C incrementally reduces its modulation of actomyosin motion generation providing a tunable mechanism to regulate cardiac function. ..
  53. Choy L, Yeo J, Tse V, Chan S, Tse G. Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models. Int J Cardiol Heart Vasc. 2016;12:1-10 pubmed
    ..Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy. ..