Myosin binding protein C, cardiac

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Myosin binding protein C, cardiac
Protein MYBPC3 PDB 1gxe.png
PDB rendering based on 1gxe.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MYBPC3 ; CMD1MM; CMH4; FHC; LVNC10; MYBP-C
External IDs OMIM600958 MGI102844 HomoloGene215 GeneCards: MYBPC3 Gene
RNA expression pattern
PBB GE MYBPC3 208040 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4607 17868
Ensembl ENSG00000134571 ENSMUSG00000002100
UniProt Q14896 O70468
RefSeq (mRNA) NM_000256 NM_008653
RefSeq (protein) NP_000247 NP_032679
Location (UCSC) Chr 11:
47.35 – 47.37 Mb
Chr 2:
91.12 – 91.14 Mb
PubMed search [1] [2]

The MYBPC3 gene encodes the protein cardiac myosin binding protein-C (cMyBP-C)[1] This isoform is expressed exclusively in heart muscle, and is distinct from those expressed in slow skeletal muscle (MYBPC1) and fast skeletal muscle (MYBPC2).[2]

Structure[edit]

cMyBP-C is a 140.5 kDa protein composed of 1273 amino acids.[3][4] cMyBP-C is a myosin-associated protein that binds at 43 nm intervals along the myosin thick filament backbone, stretching for 200 nm on either side of the M-line within the crossbridge-bearing zone (C-region) of the A band in striated muscle.[5] The approximate stoichiometry of cMyBP-C along the thick filament is 1 per 9-10 myosin molecules, or 37 cMyBP-C molecules per thick filament.[6] In addition to myosin, cMyBP-C also binds titin and actin.[7][8] The cMyBP-C isoform expressed in cardiac muscle differs from those expressed in slow and fast skeletal muscle (MYBPC1 and MYBPC2, respectively) by three features: (1) an additional immunoglobulin (Ig)-like domain on the N-terminus, (2) a linker region between the second and third Ig domains, and (3) an additional loop in the sixth Ig domain.[9] cMyBP-C appears necessary for normal order, filament length and lattice spacing within the structure of the sarcomere.[10][11]

Function[edit]

cMyBP-C appears to act as a brake on cardiac contraction, as loaded shortening, power and cycling kinetics all increase in cMyBP-C knockout mice.[12] Consistent with this notion, cMyBP-C knockout mice exhibit an abnormal systolic timecourse, with a shortened elastance timecourse and lower peak elastance in vivo,[13] and an accelerated force development in isolated, skinned cardiac fibers[14] suggesting that cMyBP-C is required to constrain the crossbridges in order to sustain a normal ejection. The linker region between the second and third Ig domains houses cAMP-dependent protein kinase (PKA) phosphorylation sites, and regulatory phosphorylation of the cardiac isoform in vivo by upon adrenergic stimulation may be linked to modulation of cardiac contraction .

Clinical significance[edit]

Mutations in MYBPC3 have been linked to familial hypertrophic cardiomyopathy, with the first being identified in 1995.[15][16] To date, roughly 200 mutations in cMyBP-C have been identified, and in large part, the mutations result in protein truncation, shifts in reading frames, and premature termination codons.[17]

References[edit]

  1. ^ Gautel M, Zuffardi O, Freiburg A, Labeit S (May 1995). "Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction?". EMBO J. 14 (9): 1952–60. PMC 398294. PMID 7744002. 
  2. ^ Carrier L, Hengstenberg C, Beckmann JS, Guicheney P, Dufour C, Bercovici J, Dausse E, Berebbi-Bertrand I, Wisnewsky C, Pulvenis D (July 1993). "Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11". Nat. Genet. 4 (3): 311–3. doi:10.1038/ng0793-311. PMID 8358441. 
  3. ^ "Protein Information - Myosin-binding protein C, cardiac-type". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). NHLBI Proteomics Center at UCLA. Retrieved 29 April 2015. 
  4. ^ Zong, N. C.; Li, H; Li, H; Lam, M. P.; Jimenez, R. C.; Kim, C. S.; Deng, N; Kim, A. K.; Choi, J. H.; Zelaya, I; Liem, D; Meyer, D; Odeberg, J; Fang, C; Lu, H. J.; Xu, T; Weiss, J; Duan, H; Uhlen, M; Yates Jr, 3rd; Apweiler, R; Ge, J; Hermjakob, H; Ping, P (2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.  edit
  5. ^ Bennett, P; Craig, R; Starr, R; Offer, G (1986). "The ultrastructural location of C-protein, X-protein and H-protein in rabbit muscle". Journal of muscle research and cell motility 7 (6): 550–67. PMID 3543050.  edit
  6. ^ Offer, G; Moos, C; Starr, R (1973). "A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization". Journal of molecular biology 74 (4): 653–76. PMID 4269687.  edit
  7. ^ 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". European journal of biochemistry / FEBS 235 (1-2): 317–23. PMID 8631348.  edit
  8. ^ Shaffer, J. F.; Kensler, R. W.; Harris, S. P. (2009). "The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner". Journal of Biological Chemistry 284 (18): 12318–27. doi:10.1074/jbc.M808850200. PMC 2673300. PMID 19269976.  edit
  9. ^ Winegrad, S (1999). "Cardiac myosin binding protein C". Circulation research 84 (10): 1117–26. PMID 10347086.  edit
  10. ^ Koretz, J. F. (1979). "Effects of C-protein on synthetic myosin filament structure". Biophysical Journal 27 (3): 433–46. doi:10.1016/S0006-3495(79)85227-3. PMC 1328598. PMID 263692.  edit
  11. ^ Colson, B. A.; Bekyarova, T; Fitzsimons, D. P.; Irving, T. C.; Moss, R. L. (2007). "Radial displacement of myosin cross-bridges in mouse myocardium due to ablation of myosin binding protein-C". Journal of Molecular Biology 367 (1): 36–41. doi:10.1016/j.jmb.2006.12.063. PMC 1892277. PMID 17254601.  edit
  12. ^ Korte, F. S.; McDonald, K. S.; Harris, S. P.; Moss, R. L. (2003). "Loaded shortening, power output, and rate of force redevelopment are increased with knockout of cardiac myosin binding protein-C". Circulation Research 93 (8): 752–8. doi:10.1161/01.RES.0000096363.85588.9A. PMID 14500336.  edit
  13. ^ Palmer, B. M.; Georgakopoulos, D; Janssen, P. M.; Wang, Y; Alpert, N. R.; Belardi, D. F.; Harris, S. P.; Moss, R. L.; Burgon, P. G.; Seidman, C. E.; Seidman, J. G.; Maughan, D. W.; Kass, D. A. (2004). "Role of cardiac myosin binding protein C in sustaining left ventricular systolic stiffening". Circulation Research 94 (9): 1249–55. doi:10.1161/01.RES.0000126898.95550.31. PMID 15059932.  edit
  14. ^ Stelzer, J. E.; Fitzsimons, D. P.; Moss, R. L. (2006). "Ablation of myosin-binding protein-C accelerates force development in mouse myocardium". Biophysical Journal 90 (11): 4119–27. doi:10.1529/biophysj.105.078147. PMC 1459529. PMID 16513777.  edit
  15. ^ Watkins, H; Conner, D; Thierfelder, L; Jarcho, J. A.; MacRae, C; McKenna, W. J.; Maron, B. J.; Seidman, J. G.; Seidman, C. E. (1995). "Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy". Nature Genetics 11 (4): 434–7. doi:10.1038/ng1295-434. PMID 7493025.  edit
  16. ^ Bonne, G; Carrier, L; Bercovici, J; Cruaud, C; Richard, P; Hainque, B; Gautel, M; Labeit, S; James, M; Beckmann, J; Weissenbach, J; Vosberg, H. P.; Fiszman, M; Komajda, M; Schwartz, K (1995). "Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy". Nature Genetics 11 (4): 438–40. doi:10.1038/ng1295-438. PMID 7493026.  edit
  17. ^ Harris, S. P.; Lyons, R. G.; Bezold, K. L. (2011). "In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament". Circulation Research 108 (6): 751–64. doi:10.1161/CIRCRESAHA.110.231670. PMC 3076008. PMID 21415409.  edit

Further reading[edit]

External links[edit]