Biology:MYL4

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 "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. doi:10.1016/S0021-9258(18)68333-4. PMID 3417683. 
  2. ↑ "Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4635. 
  3. ↑ "Protein sequence of human MYL4 (Uniprot ID: P12829)". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P12829. 
  4. ↑ "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. doi:10.1016/0022-2836(90)90261-J. PMID 2308163. 
  5. ↑ 5.0 5.1 5.2 "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. doi:10.1046/j.1432-1327.1998.2550654.x. PMID 9738905. 
  6. ↑ 6.0 6.1 "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. doi:10.1074/jbc.274.26.18271. PMID 10373429. 
  7. ↑ "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. doi:10.1128/mcb.15.8.4585. PMID 7623850. 
  8. ↑ 8.0 8.1 "Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot". Cardiovascular Research 20 (11): 828–36. November 1986. doi:10.1093/cvr/20.11.828. PMID 3621284. 
  9. ↑ "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. doi:10.1161/01.res.58.6.846. PMID 3719931. 
  10. ↑ "Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis". Development 130 (24): 6111–9. December 2003. doi:10.1242/dev.00831. PMID 14573518. 
  11. ↑ 11.0 11.1 "Regulation of human heart contractility by essential myosin light chain isoforms". The Journal of Clinical Investigation 98 (2): 467–73. July 1996. doi:10.1172/JCI118813. PMID 8755658. 
  12. ↑ "Different actin affinities of human cardiac essential myosin light chain isoforms". FEBS Letters 408 (1): 71–4. May 1997. doi:10.1016/s0014-5793(97)00390-6. PMID 9180271. 
  13. ↑ 13.0 13.1 "Distinct interactions between actin and essential myosin light chain isoforms". Biochemical and Biophysical Research Communications 449 (3): 284–8. July 2014. doi:10.1016/j.bbrc.2014.05.040. PMID 24857983. 
  14. ↑ "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. doi:10.1074/jbc.M009975200. PMID 11432848. 
  15. ↑ "Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice". The Journal of Clinical Investigation 101 (12): 2630–9. June 1998. doi:10.1172/JCI2825. PMID 9637696. 
  16. ↑ "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. doi:10.1007/s00109-004-0525-4. PMID 14985854. 
  17. ↑ "Human atrial myosin light chain 1 expression attenuates heart failure". Sliding Filament Mechanism in Muscle Contraction. 565. 2005. 283–92; discussion 92, 405–15. doi:10.1007/0-387-24990-7_21. ISBN 978-0-387-24989-6. https://archive.org/details/slidingfilamentm00musc/page/283. 
  18. ↑ "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. doi:10.1161/01.res.70.5.1035. PMID 1533180. 
  19. ↑ "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. doi:10.1093/eurheartj/5.suppl_f.85. PMID 6241906. http://doc.rero.ch/record/290166/files/5-suppl_F-85.pdf. 
  20. ↑ "Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms". Cardiovascular Research 37 (2): 381–404. February 1998. doi:10.1016/s0008-6363(97)00258-7. PMID 9614495. 
  21. ↑ "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. doi:10.1006/jmcc.1996.0353. PMID 9160869. 
  22. ↑ "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. doi:10.1007/s001099900030. PMID 10569205. 
  23. ↑ "A molecular mechanism improving the contractile state in human myocardial hypertrophy". Experimental and Clinical Cardiology 7 (2–3): 151–7. 2002. PMID 19649240. 
  24. ↑ "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. doi:10.1097/00029330-200611010-00004. PMID 17097032. 
  25. ↑ "Three-dimensional structure of myosin subfragment-1: a molecular motor". Science 261 (5117): 50–8. July 1993. doi:10.1126/science.8316857. PMID 8316857. 
  26. ↑ "Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity". Cardiovascular Research 90 (3): 513–20. June 2011. doi:10.1093/cvr/cvr026. PMID 21262909. 

Further reading




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