Myosin binding protein-C: an essential protein in skeletal and cardiac muscle.

Myosin binding protein C (MyBP-C, also known as C-protein), was discovered in skeletal muscle nearly 40 years ago (Offer et al. 1973). It is a major component of the sarcomere that is located on 7–9 stripes of 43 nm spacing in each half of the A-band as shown by immunolabelling and electron microscopy (Bennett et al. 1986). There are three isoforms, slow skeletal, fast skeletal and cardiac muscle, encoded by the genes MYBPC1 (Furst et al. 1992), MYBPC2 (Weber et al. 1993) and MYBPC3 (Gautel et al. 1995), respectively. Two key publications in 1995 reported that mutations in cardiac MyBP-C (cMyBP-C) are a major cause of hypertrophic cardiomyopathy (HCM) (Bonne et al. 1995; Watkins et al. 1995), a disease that we now know affects 1% of the world’s population (Barefield and Sadayappan 2010). This heralded massive research efforts to understand the role of cMyBP-C in the myocardium. The function of cMyBP-C is not completely understood, but it is thought to be involved in filament assembly and in regulation of cardiac contraction (Flashman et al. 2004; Oakley et al. 2004). In comparison, the skeletal isoforms (slow skeletal, ssMyBP-C; fast skeletal, fsMyBPC) have not received the same level of scrutiny, possibly because no associated skeletal myopathies have so far been reported. All that is now set to change with the new study by Gurnett et al. (2010) showing skeletal muscle disorder resulting from mutations in skeletal MyBP-C. All three isoforms of MyBP-C share a conserved domain architecture, composed of seven immunoglobulin (IgI) domains and three fibronectin type III (FnIII) domains depicted as C1-C10 (Fig. 1), with a 105 residue region between C1 and C2 called the MyBP-C motif and a prolineand alanine-rich (PA) region near the N-terminus. MyBP-C binds to LMM and titin via its C-terminal domains C7 to C10 (Okagaki et al. 1993; Freiburg and Gautel 1996). The cardiac isoform differs from the skeletal isoform in three major ways: cMyBP-C has an additional Ig domain, C0, at the N-terminus; it has 4 phosphorylation sites in the MyBP-C motif and the domain C5 has a proline-rich 25 residue insertion (Gautel et al. 1995; Barefield and Sadayappan 2010). cMyBP-C phosphorylation has a major role in regulating myocardial function and is cardioprotective (McClellan et al. 2001; Sadayappan et al. 2006). Mutations causing HCM have been found along the whole length of the cMyBP-C protein. Of the 165 MYBPC3 mutations found so far (Alcalai et al. 2008), 70% are nonsense or frame shift mutations, expected to result in truncated proteins. These truncated proteins have so far been undetectable in myocardial samples (Marston et al. 2009). Studying two familial cases of distal arthrogryposis type 1 (DA1), Gurnett et al. (2010) have now identified the first MyBP-C mutations to affect skeletal muscle, both of them missense mutations in the slow-twitch skeletal MYBPC1 gene. In this rare disease which affects 1 in 10,000, there is congenital contracture of distal limbs resulting from various intrinsic and extrinsic factors that restrict movement of the foetus in the uterus. However no additional anomalies are observed (Gurnett et al. 2010). Interestingly, other protein mutations implicated in the disease, which include Commentary for Journal of Muscle Research and Cell Motility on: Gurnett, C.A., D.M. Desruisseau, K. McCall, R. Choi, Z.I. Meyer, M. Talerico, S.E. Miller, J.S. Ju, A. Pestronk, A.M. Connolly, T.E. Druley, C.C. Weihl, and M.B. Dobbs Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet. 19:1165–1173.