MYL4

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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:

References

  1. 1.0 1.1 Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y (September 1988). "Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones". The Journal of Biological Chemistry. 263 (27): 13930–6. PMID 3417683.
  2. "Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic".
  3. "Protein sequence of human MYL4 (Uniprot ID: P12829)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 30 June 2015.
  4. 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.
  5. 5.0 5.1 5.2 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 / FEBS. 255 (3): 654–62. doi:10.1046/j.1432-1327.1998.2550654.x. PMID 9738905.
  6. 6.0 6.1 Timson DJ, Trayer HR, Smith KJ, Trayer IP (June 1999). "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. doi:10.1074/jbc.274.26.18271. PMID 10373429.
  7. Catala F, Wanner R, Barton P, Cohen A, Wright W, Buckingham M (August 1995). "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. doi:10.1128/mcb.15.8.4585. PMC 230699. PMID 7623850.
  8. 8.0 8.1 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.
  9. Cummins P, Lambert SJ (June 1986). "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. doi:10.1161/01.res.58.6.846. PMID 3719931.
  10. Huang C, Sheikh F, Hollander M, Cai C, Becker D, Chu PH, Evans S, Chen J (December 2003). "Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis". Development. 130 (24): 6111–9. doi:10.1242/dev.00831. PMID 14573518.
  11. 11.0 11.1 Morano M, Zacharzowski U, Maier M, Lange PE, Alexi-Meskishvili V, Haase H, Morano I (July 1996). "Regulation of human heart contractility by essential myosin light chain isoforms". The Journal of Clinical Investigation. 98 (2): 467–73. doi:10.1172/JCI118813. PMC 507451. PMID 8755658.
  12. Morano I, Haase H (May 1997). "Different actin affinities of human cardiac essential myosin light chain isoforms". FEBS Letters. 408 (1): 71–4. doi:10.1016/s0014-5793(97)00390-6. PMID 9180271.
  13. 13.0 13.1 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.
  14. Sanbe A, Gulick J, Fewell J, Robbins J (August 2001). "Examining the in vivo role of the amino terminus of the essential myosin light chain". The Journal of Biological Chemistry. 276 (35): 32682–6. doi:10.1074/jbc.M009975200. PMID 11432848.
  15. Fewell JG, Hewett TE, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J (June 1998). "Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice". The Journal of Clinical Investigation. 101 (12): 2630–9. doi:10.1172/JCI2825. PMC 508853. PMID 9637696.
  16. 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.
  17. Abdelaziz AI, Pagel I, Schlegel WP, Kott M, Monti J, Haase H, Morano I (2005). "Human atrial myosin light chain 1 expression attenuates heart failure". Advances in Experimental Medicine and Biology. 565: 283–92, discussion 92, 405–15. doi:10.1007/0-387-24990-7_21. PMID 16106982.
  18. Sütsch G, Brunner UT, von Schulthess C, Hirzel HO, Hess OM, Turina M, Krayenbuehl HP, Schaub MC (May 1992). "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. doi:10.1161/01.res.70.5.1035. PMID 1533180.
  19. Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO (December 1984). "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. doi:10.1093/eurheartj/5.suppl_f.85. PMID 6241906.
  20. Schaub MC, Hefti MA, Zuellig RA, Morano I (February 1998). "Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms". Cardiovascular Research. 37 (2): 381–404. doi:10.1016/s0008-6363(97)00258-7. PMID 9614495.
  21. 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.
  22. 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.
  23. Ritter O, Bottez N, Burkard N, Schulte HD, Neyses L (2002). "A molecular mechanism improving the contractile state in human myocardial hypertrophy". Experimental and Clinical Cardiology. 7 (2–3): 151–7. PMC 2719172. PMID 19649240.
  24. 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. PMID 17097032.
  25. Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM (July 1993). "Three-dimensional structure of myosin subfragment-1: a molecular motor". Science. 261 (5117): 50–8. doi:10.1126/science.8316857. PMID 8316857.
  26. Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I (June 2011). "Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity". Cardiovascular Research. 90 (3): 513–20. doi:10.1093/cvr/cvr026. PMID 21262909.

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