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Myosin binding protein-C

Myosin binding protein C (MyBP-C or C-protein as it was originally called) is responsible for the 7 fine stripes pointed by the arrows in this electron micrograph of frog sartorius muscle. Discovered ~40 years ago by Offer and colleagues (Offer et al, 1973), we do not know what the function of MyBP-C is; we believe that it has a structural role and a role in regulating (fine-tuning) contraction.  In cardiac muscle (which has 9 such stripes - see Luther et al (2008)), mutations in MyBP-C are a major cause of heart disease characterised by enlarged heart walls (hypertrophic cardiomyopathy, HCM).  HCM has high prevalence, 1 in 500 in the west, but in parts of south-east Asia, it is as high as 1 in 25 (Dhandapany et al, 2009). This has massive economic cost hence understanding the function of MyBP-C, how mutations lead to HCM and devising new therapies is of great importance.  In skeletal muscle, mutations in MyBP-C lead to foot and hand abnormalities (e.g. club-foot) (Gurnett et al, 2010; Luther and Vydyanath, 2011) underlying the importance of the protein in normal functioning of muscle.

MyBP-C can be likened to beads on a necklace; the beads are 10 kD, ~100 amino acid domains of the immunoglobulin (Ig) and fibronectin (FN3) family.  The domain structure of the cardiac and skeletal forms are identical; however the cardiac isoform has additional important properties: it has an additional Ig domain C0 at the N-terminus and has 4 phophorylation sites in the MyBP-C mofit (also called M-domain).  There are nearly 200 mutations (missense and point) in cMyBP-C and they occur over the whole molecule. 

The other proteins in muscle with similar structure are titin and myomesin.  Titin is a giant 3 MDa protein which spans half sarcomeres from the M-band to the Z-disc.  Myomesin is an important crosslinking protein in the M-band.  Understanding the properties of the Ig and FN3 domain is of fundamental importance.  The atomic structure of the Ig domain was first solved for telokin, which forms the C-terminal domain myosin light chain kinase.  Lata Govada et al have solved the atomic structure for domain C1 and Mark Pfuhl and colleagues have solved the NMR structure of domains C0, C1, C2 and C5. 


To Do

Importance of Phosphorylation of cardiac MyBP-C

Structure of MyBP-C

AFM experiments on mechanical properties of MyBP-C


Dhandapany PS, et al. (2009) A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 41:187-191.

Govada, L., et al. (2008) Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy.  J Mol Biol 378(2):387-397.

Gurnett, C.A., et al. (2010) Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet. 19:1165-73.

Luther PK, et al. (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.

Luther, P. K. and A. Vydyanath (2011). "Myosin binding protein-C: an essential protein in skeletal and cardiac muscle." J Muscle Res Cell Motil 31(5-6): 303-305.

Offer, G., et al. (1973) A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization. J Mol Biol. 74:653-76.