MYL4 explained

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.^{[1] [2]} 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.

Structure

ALC-1 is a 21.6 kDa protein composed of 197 amino acids.^[3] ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue.^[1] 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.^[4] 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.^{[5] [6]}

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.^[7] ALC-1 expression in cardiac ventricles decreases in early postnatal development, but is highly expressed in atria throughout all of adulthood.^{[8] [9]} Normal atrial function is essential for embryogenesis, as inactivation of the MYL7 gene was embryonic lethal at ED10.5-11.5.^[10]

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.^[11] Further biochemical studies unveiled a weaker binding of the Alanine-Proline-rich N-terminus of ALC-1^[5] to the C-terminus of actin relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics.^{[12] [13]} The importance of this region has however raised skepticism.^[14] 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.^[15] 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.^[16] 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.^[17]

Clinical significance

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.^[8] Altered ALC-1 expression is also altered in other congenital heart diseases, Double outlet right ventricle and infundibular pulmonary stenosis.^[11] 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.^[18]

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.^{[19] [20] [21] [22] [23]}

Interactions

ALC-1 interacts with:

• ACTC1^{[5] [6] [13]}
• MYH7^{[24] [25] [26]}

Further reading

• Rotter M, Zimmerman K, Poustka A, Soussi-Yanicostas N, Starzinski-Powitz A . The human embryonic myosin alkali light chain gene: use of alternative promoters and 3' non-coding regions . Nucleic Acids Research . 19 . 7 . 1497–504 . April 1991 . 2027757 . 333907 . 10.1093/nar/19.7.1497 .
• Seharaseyon J, Bober E, Hsieh CL, Fodor WL, Francke U, Arnold HH, Vanin EF . Human embryonic/atrial myosin alkali light chain gene: characterization, sequence, and chromosomal location . Genomics . 7 . 2 . 289–93 . June 1990 . 2129532 . 10.1016/0888-7543(90)90554-8 .
• Seidel U, Bober E, Winter B, Lenz S, Lohse P, Goedde HW, Grzeschik KH, Arnold HH . 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 . June 1988 . 2458299 . 10.1016/0378-1119(88)90231-4 .
• Arnold HH, Lohse P, Seidel U, Bober E . 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 . December 1988 . 2849544 . 10.1111/j.1432-1033.1988.tb14428.x . free .
• Strohman RC, Micou-Eastwood J, Glass CA, Matsuda R . Human fetal muscle and cultured myotubes derived from it contain a fetal-specific myosin light chain . Science . 221 . 4614 . 955–7 . September 1983 . 6879193 . 10.1126/science.6879193 . 1983Sci...221..955S .
• Timson DJ, Trayer IP . 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 . Jan 1997 . 9000508 . 10.1016/S0014-5793(96)01314-2 . 28266152 . free .
• Morano I . Tuning the human heart molecular motors by myosin light chains . Journal of Molecular Medicine . 77 . 7 . 544–55 . July 1999 . 10494800 . 10.1007/s001099900031 . 23819033 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Arrell DK, Neverova I, Fraser H, Marbán E, Van Eyk JE . Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1 . Circulation Research . 89 . 6 . 480–7 . September 2001 . 11557734 . 10.1161/hh1801.097240 . free .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• 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 . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–8 . Jan 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .

Notes and References

1. Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y . Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones . The Journal of Biological Chemistry . 263 . 27 . 13930–6 . September 1988 . 10.1016/S0021-9258(18)68333-4 . 3417683 . free .
2. Web site: Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic.
3. Web site: Protein sequence of human MYL4 (Uniprot ID: P12829). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 30 June 2015.
4. Zimmermann K, Kautz S, Hajdu G, Winter C, Whalen RG, Starzinski-Powitz A . 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 . February 1990 . 2308163 . 10.1016/0022-2836(90)90261-J .
5. Timson DJ, Trayer HR, Trayer IP . 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 . August 1998 . 9738905 . 10.1046/j.1432-1327.1998.2550654.x.
6. Timson DJ, Trayer HR, Smith KJ, Trayer IP . Size and charge requirements for kinetic modulation and actin binding by alkali 1-type myosin essential light chains . The Journal of Biological Chemistry . 274 . 26 . 18271–7 . June 1999 . 10373429 . 10.1074/jbc.274.26.18271. free .
7. Catala F, Wanner R, Barton P, Cohen A, Wright W, Buckingham M . A skeletal muscle-specific enhancer regulated by factors binding to E and CArG boxes is present in the promoter of the mouse myosin light-chain 1A gene . Molecular and Cellular Biology . 15 . 8 . 4585–96 . August 1995 . 7623850 . 10.1128/mcb.15.8.4585 . 230699.
8. Auckland LM, Lambert SJ, Cummins P . Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot . Cardiovascular Research . 20 . 11 . 828–36 . November 1986 . 3621284 . 10.1093/cvr/20.11.828.
9. Cummins P, Lambert SJ . Myosin transitions in the bovine and human heart. A developmental and anatomical study of heavy and light chain subunits in the atrium and ventricle . Circulation Research . 58 . 6 . 846–58 . June 1986 . 3719931 . 10.1161/01.res.58.6.846. free .
10. Huang C, Sheikh F, Hollander M, Cai C, Becker D, Chu PH, Evans S, Chen J . Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis . Development . 130 . 24 . 6111–9 . December 2003 . 14573518 . 10.1242/dev.00831 . free .
11. Morano M, Zacharzowski U, Maier M, Lange PE, Alexi-Meskishvili V, Haase H, Morano I . Regulation of human heart contractility by essential myosin light chain isoforms . The Journal of Clinical Investigation . 98 . 2 . 467–73 . July 1996 . 8755658 . 10.1172/JCI118813 . 507451.
12. Morano I, Haase H . Different actin affinities of human cardiac essential myosin light chain isoforms . FEBS Letters . 408 . 1 . 71–4 . May 1997 . 9180271 . 10.1016/s0014-5793(97)00390-6. 22222814 .
13. Petzhold D, Simsek B, Meißner R, Mahmoodzadeh S, Morano I . Distinct interactions between actin and essential myosin light chain isoforms . Biochemical and Biophysical Research Communications . 449 . 3 . 284–8 . July 2014 . 24857983 . 10.1016/j.bbrc.2014.05.040 .
14. Sanbe A, Gulick J, Fewell J, Robbins J . Examining the in vivo role of the amino terminus of the essential myosin light chain . The Journal of Biological Chemistry . 276 . 35 . 32682–6 . August 2001 . 11432848 . 10.1074/jbc.M009975200 . free.
15. Fewell JG, Hewett TE, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J . Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice . The Journal of Clinical Investigation . 101 . 12 . 2630–9 . June 1998 . 9637696 . 10.1172/JCI2825 . 508853.
16. Abdelaziz AI, Segaric J, Bartsch H, Petzhold D, Schlegel WP, Kott M, Seefeldt I, Klose J, Bader M, Haase H, Morano I . 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 . April 2004 . 14985854 . 10.1007/s00109-004-0525-4 . 19506306 .
17. Book: Abdelaziz AI, Pagel I, Schlegel WP, Kott M, Monti J, Haase H, Morano I . Sliding Filament Mechanism in Muscle Contraction . Human atrial myosin light chain 1 expression attenuates heart failure . Advances in Experimental Medicine and Biology . 565 . 283–92; discussion 92, 405–15 . 2005 . Springer . 16106982 . 10.1007/0-387-24990-7_21 . 978-0-387-24989-6 . registration . https://archive.org/details/slidingfilamentm00musc/page/283 .
18. Sütsch G, Brunner UT, von Schulthess C, Hirzel HO, Hess OM, Turina M, Krayenbuehl HP, Schaub MC . Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement . Circulation Research . 70 . 5 . 1035–43 . May 1992 . 1533180 . 10.1161/01.res.70.5.1035. free .
19. Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO . Myosin isoenzymes in human hypertrophic hearts. Shift in atrial myosin heavy chains and in ventricular myosin light chains . European Heart Journal . 5 Suppl F . 85–93 . December 1984 . 6241906 . 10.1093/eurheartj/5.suppl_f.85.
20. Schaub MC, Hefti MA, Zuellig RA, Morano I . Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms . Cardiovascular Research . 37 . 2 . 381–404 . February 1998 . 9614495 . 10.1016/s0008-6363(97)00258-7. free .
21. Morano I, Hädicke K, Haase H, Böhm M, Erdmann E, Schaub MC . 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 . April 1997 . 9160869 . 10.1006/jmcc.1996.0353 .
22. Ritter O, Luther HP, Haase H, Baltas LG, Baumann G, Schulte HD, Morano I . 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 . September 1999 . 10569205 . 10.1007/s001099900030. 19888645 .
23. Ritter O, Bottez N, Burkard N, Schulte HD, Neyses L . A molecular mechanism improving the contractile state in human myocardial hypertrophy . Experimental and Clinical Cardiology . 7 . 2–3 . 151–7 . 2002 . 19649240 . 2719172.
24. Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM, Jiang WP . Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy . Chinese Medical Journal . 119 . 21 . 1785–9 . November 2006 . 17097032 . 10.1097/00029330-200611010-00004 . free .
25. Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM . Three-dimensional structure of myosin subfragment-1: a molecular motor . Science . 261 . 5117 . 50–8 . July 1993 . 8316857 . 10.1126/science.8316857. 1993Sci...261...50R .
26. Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I . Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity . Cardiovascular Research . 90 . 3 . 513–20 . June 2011 . 21262909 . 10.1093/cvr/cvr026 . free .