ALC-1 is a 21.6 kDa protein composed of 197 amino acids.[7] ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue.[5] ALC-1 binds the neck region of muscle myosin in adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.[8] Relative to ventricular essential light chain VLC-1, ALC-1 has an additional ~40 amino-acid N-terminal region that contains four to eleven residues that are critical for binding actin and modulating myosin kinetics.[9][10]
Function
ALC-1 is expressed very early in skeletal muscle and cardiac muscle development; two E-boxes and CArG box in the MYL4 promoter region regulate transcription.[11] ALC-1 expression in cardiac ventricles decreases in early postnatal development, but is highly expressed in atria throughout all of adulthood.[12][13] Normal atrial function is essential for embryogenesis, as inactivation of the MYL7 gene was embryonic lethal at ED10.5-11.5.[14]
Evidence of ALC-1 isoform expression on contractile mechanics of sarcomeres came from experiments studying fibers from patients expressing a higher level of ALC-1 relative to VLC-1 in cardiac left ventricular tissue. Fibers expressing high ALC-1 exhibited a higher maximal velocity and rate of shortening compared to fibers with low amounts of ALC-1, suggesting that ALC-1 increases cycling kinetics of myosin cross-bridges and regulates cardiac contractility.[15] Further biochemical studies unveiled a weaker binding of the Alanine-Proline-rich N-terminus of ALC-1[9] to the C-terminus of actin relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics.[16][17] The importance of this region has however raised skepticism.[18] Further evidence for the contractile-enhancing properties of ALC-1 came from studies employing transgenesis to replace VLC-1 with ALC-1 in the mouse ventricle. This study demonstrated an increase in unloaded shortening velocity, both in skinned fibers and in an in vitro motility assay, as well as enhanced contractility and relaxation in whole heart experiments.[19] These studies were supported by further studies in transgenic rats overexpressing ALC-1 which showed enhanced rates of contraction and relaxation, as well as left ventricular developed pressure in Langendorff heart preparations.[20] Importantly, overexpression of ALC-1 was shown to attenuate heart failure in pressure-overloaded animals, by enhancing left ventricular developed pressure, maximal velocity of pressure development and relaxation.[21]
^Zimmermann K, Kautz S, Hajdu G, Winter C, Whalen RG, Starzinski-Powitz A (February 1990). "Heterogenic mRNAs with an identical protein-coding region of the human embryonic myosin alkali light chain in skeletal muscle cells". Journal of Molecular Biology. 211 (3): 505–13. doi:10.1016/0022-2836(90)90261-J. PMID2308163.
^ abcTimson DJ, Trayer HR, Trayer IP (August 1998). "The N-terminus of A1-type myosin essential light chains binds actin and modulates myosin motor function". European Journal of Biochemistry. 255 (3): 654–62. doi:10.1046/j.1432-1327.1998.2550654.x. PMID9738905.
^Abdelaziz AI, Segaric J, Bartsch H, Petzhold D, Schlegel WP, Kott M, Seefeldt I, Klose J, Bader M, Haase H, Morano I (April 2004). "Functional characterization of the human atrial essential myosin light chain (hALC-1) in a transgenic rat model". Journal of Molecular Medicine. 82 (4): 265–74. doi:10.1007/s00109-004-0525-4. PMID14985854. S2CID19506306.
^Morano I, Hädicke K, Haase H, Böhm M, Erdmann E, Schaub MC (April 1997). "Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart". Journal of Molecular and Cellular Cardiology. 29 (4): 1177–87. doi:10.1006/jmcc.1996.0353. PMID9160869.
^Ritter O, Luther HP, Haase H, Baltas LG, Baumann G, Schulte HD, Morano I (September 1999). "Expression of atrial myosin light chains but not alpha-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy". Journal of Molecular Medicine. 77 (9): 677–85. doi:10.1007/s001099900030. PMID10569205. S2CID19888645.
Seharaseyon J, Bober E, Hsieh CL, Fodor WL, Francke U, Arnold HH, Vanin EF (June 1990). "Human embryonic/atrial myosin alkali light chain gene: characterization, sequence, and chromosomal location". Genomics. 7 (2): 289–93. doi:10.1016/0888-7543(90)90554-8. PMID2129532.
Seidel U, Bober E, Winter B, Lenz S, Lohse P, Goedde HW, Grzeschik KH, Arnold HH (June 1988). "Alkali myosin light chains in man are encoded by a multigene family that includes the adult skeletal muscle, the embryonic or atrial, and nonsarcomeric isoforms". Gene. 66 (1): 135–46. doi:10.1016/0378-1119(88)90231-4. PMID2458299.
