Abstract
The 3D structure of Type-II myosin comprises the bell-shaped motor domain and the alpha-helical neck domain associated with an essential light chain (ELC) and a regulatory light chain (subfragment-1 (S1). A large part of the N-terminus of the ELC (46 amino acids) is missing in this model which therefore resembles the spliced ELC isoform (A2) of fast-twitch skeletal muscle. We modelled the missing 46 N-terminal amino acid to the ELC of the contemporary 3D model of myosin-S2 in order to yield S1 (A1). The missing 46 amino acids revealed an elongated structure with a length of 9.1 nm, i.e. long enough to bridge the gap between A2 and the corresponding ELC binding site on the actin filament. In addition, we generated transgenic rats (TGR) which over-expressed N-terminal 15 amino acids of human atrial A1or human ventricular A1 isoforms in cardiomyocytes. Corresponding synthetic N-terminal peptides revealed specific actin binding. Expression of N-terminal human A1 peptides in TGR (range: 3–6 μM) was associated with significant (p<0.001) improvements of the intrinsic contractile state of the isolated perfused heart. Using synthetic hVLC-1/1–15 as a TAT fusion peptide, we observed specific accumulation of the peptide in the sarcomeres of cultivated adult cardiomyo-cytes as well as a dose-dependent (maximal effect at 1 μM) increase of shortening amplitude at constant activating intracellular free Ca2+.
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