Myosin heavy chain

The genetic predisposition to HCM is thought to be an autosomal dominant trait with variable penetrance. Owing to the wide variability of presentation, not aU cases in a family may be detected. HCM usually is caused by mutations in the genes for -myosin heavy chain, myosin-binding protein C, and cardiac troponin... 

All myosins consist of one or two heavy chains and several light chains, which generally have a regulatory function. A characteristic head, neck, and tail domain organization Is found In all myosin heavy chains. Myosin II and myosin V are dimers In which ct-helical sequences In the tail of each heavy chain associate to form a rodlike colled-coll structure. In contrast some myosins, including myosin I, are monomers because their heavy chains lack this ct-hellcal sequence. All myosin head domains have ATPase activity and... 

Figure 14.14 Sci ematic diagram of the myosin molecule, comprising two heavy chains (green) that form a coiled-coil tail with two globular heads and four light chains (gray) of two slightly differing sizes, each one bound to each heavy-chain globular head.

Figure 14.15 Stmcture of the SI fragment of chicken myosin as a Richardson diagram (a) and a space-filling model (b). The two light chains are shown in magenta and yellow. The heavy chain is colored according to three proteolytic fragments produced by trypsin a 25-kDa N-terminal domain (green) a central 50-kDa fragment (red) divided by a cleft into a 50K upper and a 50K lower domain and a 20-kDa C-terminal domain (blue) that links the myosin head to the coiled-coil tail. The 50-kDa and 20-kDa domains both bind actin, while the 25-kDa domain binds ATP. [(b) Courtesy of 1. Rayment.]...

NFAT proteins are expressed in skeletal, cardiac, and smooth muscle and play important roles in the regulation of the development and differentiation of these tissues. In skeletal muscle, NFAT isoforms are expressed at different stages of development and regulate progression from early muscle cell precursors to mature myocytes. NFAT proteins have also been shown to control the expression of the myosin heavy chain and positively regulate muscle growth [1, 2]. 

Nonmuscle/smooth muscle myosins-Il are structurally similar to striated muscle myosin-II, but they have slower rates of ATP hydrolysis than do their striated muscle counterparts. Nonmuscle/smooth muscle myosin-II is also regulated differently than striated muscle myosin-II. Nonmuscle myosin-II is divided into the invertebrate and vertebrate branches (Cheney et al., 1993). This group is ubiquitous because it is present in most lower organisms, such as slime molds, amoeba, sea urchins, etc., and in virtually all mammalian nonmuscle cells. Smooth muscle myosin-II is also somewhat heterogeneous in that at least three separate forms of smooth muscle heavy chains, with molecular weights of 196,000, 200,000, and 204,000 have been identified (Kawamoto and Adelstein, 1987). The physiological properties of these separate myosin heavy chains are not yet known. 

Myosin-II phosphorylation is also an important mechanism for regulating myosin assembly in nonmuscle and smooth muscle cells (Kom and Hammer, 1988). For example, myosin-II ixomAcanthamoeba is more soluble when the heavy chain is phosphorylated compared to the unphosphorylated species. Similarly, phosphorylation of the light chains of vertebrate smooth muscle and nonmuscle myosin-II affects filament formation by these myosins. These myosins undergo a... 

Myosin-I molecules have several IQ sequences on or near the head and have light chains associated with them (Cheney and Mooseker, 1992 Cheney et al., 1993). Frequently, the light chains appear to be calmodulin molecules and some myosin-I molecules can bind three to four molecules of calmodulin at one time. Brush-border and adrenal myosin-I also bind calmodulin. Acanthamoeba myosin-I has a light chain that can be removed, in vitro, without adversely affecting the ATPase activity or the heavy chain phosphorylation (Korn and Hammer, 1988). The role of these calmodulin molecules in regulating myosin-I is complex and poorly understood. One possibility is that the calmodulin molecules dissociate from the heavy chains when calcium binds to the calmodulin, thereby imparting greater flexibility to the head of the myosin-I molecules. 

The regulation of myosin-I activity is not well understood. As mentioned above, the heavy chain is phosphorylated in Acanthamoeba but the regulatory effect of this process is unclear. Myosin-I from Acanthamoeba, Dictyostelium, brush-bor-... 

De Lozanne, A. Spudich, J.A. (1987). Disruption of the Dictyostelium myosin heavy chain gene by homologous recombination. Science 236, 1086-1091. 

Geisterfer-Lowrance, A.A., Kass, S., Tanigawa, G., Vosberg, H.-P., McKenna, W., Seidman, C.E., Seidman, J.G. (1990). A molecular basis for familial hypertrophic cardiomyopathy a p-cardiac myosin heavy chain gene missense mutation. Cell 62, 999-1006,... 

Kawamoto, S. Adelstein, R.S. (1987), Characterization of myosin heavy chains in cultured aorta smooth muscle cells. A comparative study. J. Biol. Chem. 262, 7282-7288. 

Knecht, D.A., Loomis, W.F. (1987). Antisense RNA inactivation of myosin heavy chain gene expression in Dictyostelium discoideum. Science 236, 1081-1086. 

The crystal structure of myosin S-1 shows how the three subdomains (20K, 50K and 27K) of the myosin heavy chain (produced by further enzymatic digestion of... 

Abnormalities of myocardial contractile and structural proteins P-Myosin heavy chains, troponin, tropomyosin, dystrophin... 

Mutations in the Cardiac (i-Myosin Heavy Chain Gene Are One Cause of Familial Hypertrophic Cardiomyopathy... 

Figure 49-13. Simplified scheme of the causation of familial hypertrophic cardiomyopathy (MIM 192600) due to mutations in the gene encoding fi-myosin heavy chain. Mutations in genes encoding other proteins, such as the troponins, tropomyosin, and cardiac myosin-binding protein C can also cause this condition. Mutations in genes encoding yet other proteins (eg, dystrophin) are involved in the causation of dilated cardiomyopathy.

Some cases of famifial hypertrophic cardiomyopathy are due to missense mutations in the gene coding for p-myosin heavy chain. 

W - Dominant spotting SI = Steel a = nonagouti, d = dilute c - albino , p = pink-eyed dilution MHC = myosin heavy chain. 

---