Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a protein that in humans is encoded by the MYL4 gene.[5][6] ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular myocardium in various cardiac muscle diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and congenital heart diseases.
Quick Facts Identifiers, Aliases ...
Close
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]
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]
MYL4 expression in ventricular myocardium has shown to abnormally persist in neonates up through adulthood in patients with the congenital heart disease, tetralogy of Fallot.[12] Altered ALC-1 expression is also altered in other congenital heart diseases, Double outlet right ventricle and infundibular pulmonary stenosis.[15] Moreover, in patients with aortic stenosis or aortic insufficiency, ALC-1 expression in left ventricles was elevated, and following valve replacement decreased to lower levels; ALC-1 expression also correlated with left ventricular systolic pressure.[22]
Additionally, in patients with ischemic cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy, ALC-1 protein expression is shown to be reactivated, and ALC-1 expression correlates with calcium sensitivity of myofilament proteins in skinned fiber preparations, as well as ventricular dP/dtmax and ejection fraction.[23][24][25][26][27]
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. PMID 2308163.
Timson 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. PMID 9738905.
Auckland LM, Lambert SJ, Cummins P (November 1986). "Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot". Cardiovascular Research. 20 (11): 828–36. doi:10.1093/cvr/20.11.828. PMID 3621284.
Petzhold D, Simsek B, Meißner R, Mahmoodzadeh S, Morano I (July 2014). "Distinct interactions between actin and essential myosin light chain isoforms". Biochemical and Biophysical Research Communications. 449 (3): 284–8. doi:10.1016/j.bbrc.2014.05.040. PMID 24857983.
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. PMID 14985854. S2CID 19506306.
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. PMID 9160869.
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. PMID 10569205. S2CID 19888645.
Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM, Jiang WP (November 2006). "Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy". Chinese Medical Journal. 119 (21): 1785–9. doi:10.1097/00029330-200611010-00004. PMID 17097032.
- Rotter M, Zimmerman K, Poustka A, Soussi-Yanicostas N, Starzinski-Powitz A (April 1991). "The human embryonic myosin alkali light chain gene: use of alternative promoters and 3' non-coding regions". Nucleic Acids Research. 19 (7): 1497–504. doi:10.1093/nar/19.7.1497. PMC 333907. PMID 2027757.
- 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. PMID 2129532.
- 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. PMID 2458299.
- Arnold HH, Lohse P, Seidel U, Bober E (December 1988). "A novel human myosin alkali light chain is developmentally regulated. Expression in fetal cardiac and skeletal muscle and in adult atria". European Journal of Biochemistry. 178 (1): 53–60. doi:10.1111/j.1432-1033.1988.tb14428.x. PMID 2849544.
- Strohman RC, Micou-Eastwood J, Glass CA, Matsuda R (September 1983). "Human fetal muscle and cultured myotubes derived from it contain a fetal-specific myosin light chain". Science. 221 (4614): 955–7. Bibcode:1983Sci...221..955S. doi:10.1126/science.6879193. PMID 6879193.
- Timson DJ, Trayer IP (Jan 1997). "The rôle of the proline-rich region in A1-type myosin essential light chains: implications for information transmission in the actomyosin complex". FEBS Letters. 400 (1): 31–6. doi:10.1016/S0014-5793(96)01314-2. PMID 9000508. S2CID 28266152.
- Morano I (July 1999). "Tuning the human heart molecular motors by myosin light chains". Journal of Molecular Medicine. 77 (7): 544–55. doi:10.1007/s001099900031. PMID 10494800. S2CID 23819033.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Arrell DK, Neverova I, Fraser H, Marbán E, Van Eyk JE (September 2001). "Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1". Circulation Research. 89 (6): 480–7. doi:10.1161/hh1801.097240. PMID 11557734.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.