MYL7

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a protein that in humans is encoded by the MYL7 gene.[1][2] ALC-2 expression is restricted to cardiac muscle atria in healthy individuals, where it functions to modulate cardiac development and contractility. In human diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and others, ALC-2 expression is altered.

Structure

Human ALC-2 protein has a molecular weight of 19.4 kDa and is composed of 175 amino acids.[3] ALC-2 is an EF hand protein that binds to the neck region of alpha myosin heavy chain.[4] ALC-2 and the ventricular isoform, VLC-2, share 59% homology, showing significant differences at their N-termini and at the regulatory phosphorylation site(s), Serine-15 and Serine/Asparagine-14.[5]

Function

ALC-2 expression has proven to be a useful marker of cardiac muscle chamber distinction, development and differentiation.[6][7][8][9][10] ALC-2 shows a pattern distinct from atrial essential light chain (ALC-1) during cardiogenesis. ALC-2 expression in adult murine hearts is cardiac-specific throughout embryonic days 8-16, and from day 12 and on is restricted to atria, showing very low levels in aorta and undetectable in ventricles, skeletal muscle, uterus, and liver. This atrial patterning occurs prior to septation.[11] Expression of ALC-2 has been shown to correlate with expression of alpha-myosin heavy chain in cardiac atria of non-human primates.[12]

ALC-2 and VLC-2 appear to function in the stabilization of thick filaments and regulation of contractility in the vertebrate heart.[13] Functional insights into ALC-2 function have come from studies employing transgenesis. A study in which the ventricular isoform of regulatory light chain was overexpressed to replace the ALC-2 in cardiac atria was performed. This substitution resulted in atrial myocytes that contract and relax more forcefully and quickly, resulting in atrial cardiomyocytes that behave as ventricular cardiomyocytes.[14]

In disease models, ALC-2 expression in some instances can be downregulated and replaced by the ventricular isoform (VLC-2). In spontaneously hypertensive rats, VLC-2 mRNA expression is three times higher in atria; and this change precedes any detectable pressure overloading of the heart, suggesting that this change is a very early functional adaptation to cardiac hypertrophy.[15] Moreover, in a porcine model of atrial fibrillation, VLC-2 mRNA expression showed the greatest change, being upregulated 9.4-fold and 7.3-fold in left and right atria, respectively.[16] In a porcine model of left atrial remodeling following mitral regurgitation, VLC-2 was shown to be upregulated.[17]

Human ALC-2 is phosphorylated at its N-terminus at Serine-15 by a cardiac-specific myosin light chain kinase;[18][19] ALC-2 has a serine at position 14, which is an Asparagine in the ventricular isoform that is shown to be deamidated (thus producing a negative charge similar to phosphorylation). Whether serine-14 of human ALC-2 is also phosphorylated remains to be determined. Endogenous phosphorylation level is around 30% of the total ALC-2.[20] Alpha(1)-adrenergic stimulation by phenylephrine in atrial muscle strips showed an 80% increase in ALC-2 phosphorylation coordinate with enhanced contractile force, which was inhibited by both Rho kinase and myosin light chain kinase inhibition.[21] In a canine model of atrial fibrillation, decreased atrial contractility was associated with decreased ALC-2 and myosin binding protein C phosphorylation.[22] Moreover, the slow force response induced by stretch in human atrial muscle was shown to be modulated by enhanced phosphorylation of ALC-2 by myosin light chain kinase.[23]

Clinical Significance

Patients with hypertrophic cardiomyopathy shown an increased expression of ALC-2 in whole heart tissue.[24] In patients with mitral valve disease, ischemic cardiomyopathy, dilated cardiomyopathy, coronary heart disease and pressure overload-induced cardiac hypertrophy, ALC-2 was shown to be replaced with VLC-2 in cardiac atria; in dilated cardiomyopathy, this change was concomitant with enhanced sensitivity of atrial fibers to calcium.[25][26]

In patients with congenital atrial septal defect carrying a missense mutation Ile820Asn in alpha myosin heavy chain, it was shown that binding of ALC-2 to alpha myosin heavy chain is disrupted.[27]

Interactions

ALC-2 is shown to interact with:

References

  1. ↑ Kubalak SW, Miller-Hance WC, O'Brien TX, Dyson E, Chien KR (June 1994). "Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis". The Journal of Biological Chemistry. 269 (24): 16961–70. PMID 8207020.
  2. ↑ "Entrez Gene: MYL7 myosin, light chain 7, regulatory".
  3. ↑ "Protein sequence of human MYL7 (Uniprot ID: Q01449)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 30 June 2015.
  4. ↑ 4.0 4.1 Winkelmann DA, Baker TS, Rayment I (August 1991). "Three-dimensional structure of myosin subfragment-1 from electron microscopy of sectioned crystals". The Journal of Cell Biology. 114 (4): 701–13. doi:10.1083/jcb.114.4.701. PMC 2289899. PMID 1869586.
  5. ↑ "Protein sequence alignment for human cardiac atrial and ventricular regulatory light chains". Uniprot Knowledgebase. Retrieved 30 June 2015.[permanent dead link]
  6. ↑ Ovchinnikov DA, Hidalgo A, Yang SK, Zhang X, Hudson J, Mazzone SB, Chen C, Cooper-White JJ, Wolvetang EJ (January 2015). "Isolation of contractile cardiomyocytes from human pluripotent stem-cell-derived cardiomyogenic cultures using a human NCX1-EGFP reporter". Stem Cells and Development. 24 (1): 11–20. doi:10.1089/scd.2014.0195. PMID 25075536.
  7. ↑ Hudson J, Titmarsh D, Hidalgo A, Wolvetang E, Cooper-White J (June 2012). "Primitive cardiac cells from human embryonic stem cells". Stem Cells and Development. 21 (9): 1513–23. doi:10.1089/scd.2011.0254. PMID 21933026.
  8. ↑ Small EM, Krieg PA (January 2004). "Molecular regulation of cardiac chamber-specific gene expression". Trends in Cardiovascular Medicine. 14 (1): 13–8. doi:10.1016/j.tcm.2003.09.005. PMID 14720469.
  9. ↑ Franco D, Markman MM, Wagenaar GT, Ya J, Lamers WH, Moorman AF (January 1999). "Myosin light chain 2a and 2v identifies the embryonic outflow tract myocardium in the developing rodent heart". The Anatomical Record. 254 (1): 135–46. doi:10.1002/(sici)1097-0185(19990101)254:1<135::aid-ar17>3.3.co;2-j. PMID 9892427.
  10. ↑ Doevendans PA, Bronsaer R, Lozano PR, Kubalak S, van Bilsen M (2000). "The murine atrial myosin light chain-2 gene: a member of an evolutionarily conserved family of contractile proteins". Cytogenetics and Cell Genetics. 90 (3–4): 248–52. doi:10.1159/000056782. PMID 11124527.
  11. ↑ Kubalak SW, Miller-Hance WC, O'Brien TX, Dyson E, Chien KR (June 1994). "Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis". The Journal of Biological Chemistry. 269 (24): 16961–70. PMID 8207020.
  12. ↑ Henkel RD, Kammerer CM, Escobedo LV, VandeBerg JL, Walsh RA (March 1993). "Correlated expression of atrial myosin heavy chain and regulatory light chain isoforms with pressure overload hypertrophy in the non-human primate". Cardiovascular Research. 27 (3): 416–22. doi:10.1093/cvr/27.3.416. PMID 8490941.
  13. ↑ Rottbauer W, Wessels G, Dahme T, Just S, Trano N, Hassel D, Burns CG, Katus HA, Fishman MC (August 2006). "Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart". Circulation Research. 99 (3): 323–31. doi:10.1161/01.res.0000234807.16034.fe. PMID 16809551.
  14. ↑ Pawloski-Dahm CM, Song G, Kirkpatrick DL, Palermo J, Gulick J, Dorn GW, Robbins J, Walsh RA (April 1998). "Effects of total replacement of atrial myosin light chain-2 with the ventricular isoform in atrial myocytes of transgenic mice". Circulation. 97 (15): 1508–13. doi:10.1161/01.cir.97.15.1508. PMID 9576432.
  15. ↑ Kumar C, Saidapet C, Delaney P, Mendola C, Siddiqui MA (June 1988). "Expression of ventricular-type myosin light chain messenger RNA in spontaneously hypertensive rat atria". Circulation Research. 62 (6): 1093–7. doi:10.1161/01.res.62.6.1093. PMID 3383359.
  16. ↑ Lai LP, Lin JL, Lin CS, Yeh HM, Tsay YG, Lee CF, Lee HH, Chang ZF, Hwang JJ, Su MJ, Tseng YZ, Huang SK (February 2004). "Functional genomic study on atrial fibrillation using cDNA microarray and two-dimensional protein electrophoresis techniques and identification of the myosin regulatory light chain isoform reprogramming in atrial fibrillation". Journal of Cardiovascular Electrophysiology. 15 (2): 214–23. doi:10.1046/j.1540-8167.2004.03423.x. PMID 15028053.
  17. ↑ Chen MC, Chang JP, Chang TH, Hsu SD, Huang HD, Ho WC, Wang FS, Hsiao CC, Liu WH (May 2015). "Unraveling regulatory mechanisms of atrial remodeling of mitral regurgitation pigs by gene expression profiling analysis: role of type I angiotensin II receptor antagonist". Translational Research. 165 (5): 599–620. doi:10.1016/j.trsl.2014.11.005. PMID 25500755.
  18. ↑ Ding P, Huang J, Battiprolu PK, Hill JA, Kamm KE, Stull JT (December 2010). "Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo". The Journal of Biological Chemistry. 285 (52): 40819–29. doi:10.1074/jbc.m110.160499. PMC 3003383. PMID 20943660.
  19. ↑ Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM (September 2010). "A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain". Molecular & Cellular Proteomics. 9 (9): 1804–18. doi:10.1074/mcp.m110.000075. PMC 2938104. PMID 20445002.
  20. ↑ Svensson C, Morano I, Arner A (November 1997). "In vitro motility assay of atrial and ventricular myosin from pig". Journal of Cellular Biochemistry. 67 (2): 241–7. doi:10.1002/(sici)1097-4644(19971101)67:2<241::aid-jcb9>3.0.co;2-x. PMID 9328829.
  21. ↑ Grimm M, Haas P, Willipinski-Stapelfeldt B, Zimmermann WH, Rau T, Pantel K, Weyand M, Eschenhagen T (January 2005). "Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium". Cardiovascular Research. 65 (1): 211–20. doi:10.1016/j.cardiores.2004.09.019. PMID 15621049.
  22. ↑ Wakili R, Yeh YH, Yan Qi X, Greiser M, Chartier D, Nishida K, Maguy A, Villeneuve LR, Boknik P, Voigt N, Krysiak J, Kääb S, Ravens U, Linke WA, Stienen GJ, Shi Y, Tardif JC, Schotten U, Dobrev D, Nattel S (October 2010). "Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs". Circulation: Arrhythmia and Electrophysiology. 3 (5): 530–41. doi:10.1161/circep.109.933036. PMID 20660541.
  23. ↑ Kockskämper J, Khafaga M, Grimm M, Elgner A, Walther S, Kockskämper A, von Lewinski D, Post H, Grossmann M, Dörge H, Gottlieb PA, Sachs F, Eschenhagen T, Schöndube FA, Pieske B (September 2008). "Angiotensin II and myosin light-chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium". Cardiovascular Research. 79 (4): 642–51. doi:10.1093/cvr/cvn126. PMC 2614393. PMID 18503051.
  24. ↑ Lim DS, Roberts R, Marian AJ (October 2001). "Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes". Journal of the American College of Cardiology. 38 (4): 1175–80. doi:10.1016/s0735-1097(01)01509-1. PMC 2776821. PMID 11583900.
  25. ↑ Wankerl M, Böhm M, Morano I, Rüegg JC, Eichhorn M, Erdmann E (December 1990). "Calcium sensitivity and myosin light chain pattern of atrial and ventricular skinned cardiac fibers from patients with various kinds of cardiac disease". Journal of Molecular and Cellular Cardiology. 22 (12): 1425–38. doi:10.1016/0022-2828(90)90986-c. PMID 2089158.
  26. ↑ Cummins P (July 1982). "Transitions in human atrial and ventricular myosin light-chain isoenzymes in response to cardiac-pressure-overload-induced hypertrophy". The Biochemical Journal. 205 (1): 195–204. doi:10.1042/bj2050195. PMC 1158463. PMID 6215032.
  27. ↑ 27.0 27.1 Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD (April 2005). "Mutation in myosin heavy chain 6 causes atrial septal defect". Nature Genetics. 37 (4): 423–8. doi:10.1038/ng1526. PMID 15735645.

Further reading

  • Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD (April 2005). "Mutation in myosin heavy chain 6 causes atrial septal defect". Nature Genetics. 37 (4): 423–8. doi:10.1038/ng1526. PMID 15735645.
  • Grimm M, Haas P, Willipinski-Stapelfeldt B, Zimmermann WH, Rau T, Pantel K, Weyand M, Eschenhagen T (January 2005). "Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium". Cardiovascular Research. 65 (1): 211–20. doi:10.1016/j.cardiores.2004.09.019. PMID 15621049.
  • Kovács M, Wang F, Hu A, Zhang Y, Sellers JR (October 2003). "Functional divergence of human cytoplasmic myosin II: kinetic characterization of the non-muscle IIA isoform". The Journal of Biological Chemistry. 278 (40): 38132–40. doi:10.1074/jbc.M305453200. PMID 12847096.
  • Bird SD, Doevendans PA, van Rooijen MA, Brutel de la Riviere A, Hassink RJ, Passier R, Mummery CL (May 2003). "The human adult cardiomyocyte phenotype". Cardiovascular Research. 58 (2): 423–34. doi:10.1016/S0008-6363(03)00253-0. PMID 12757876.
  • Nishigaki R, Shinohara T, Toda T, Omori A, Ichinose S, Itoh M, Shirayoshi Y, Kurimasa A, Oshimura M (July 2002). "An extra human chromosome 21 reduces mlc-2a expression in chimeric mice and Down syndrome". Biochemical and Biophysical Research Communications. 295 (1): 112–8. doi:10.1016/S0006-291X(02)00640-X. PMID 12083776.
  • Hailstones D, Barton P, Chan-Thomas P, Sasse S, Sutherland C, Hardeman E, Gunning P (November 1992). "Differential regulation of the atrial isoforms of the myosin light chains during striated muscle development". The Journal of Biological Chemistry. 267 (32): 23295–300. PMID 1429676.
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