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{{Infobox gene}}
{{PBB_Controls
'''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]].<ref name="Kurabayashi_1988">{{cite journal | vauthors = Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y | title = Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones | journal = The Journal of Biological Chemistry | volume = 263 | issue = 27 | pages = 13930–6 | date = September 1988 | pmid = 3417683 | pmc = | doi = }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4635| accessdate = }}</ref> ALC-1 is expressed in fetal [[Ventricle (heart)|cardiac ventricular]] and fetal [[skeletal muscle]], as well as fetal and adult [[Atrium (heart)|cardiac atrial]] tissue. ALC-1 expression is reactivated in human [[ventricle (heart)|ventricular]] [[myocardium]] in various [[cardiac muscle]] diseases, including [[hypertrophic cardiomyopathy]], [[dilated cardiomyopathy]], [[ischemic cardiomyopathy]] and [[congenital heart disease]]s.
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| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
ALC-1 is a 21.6 kDa protein composed of 197 amino acids.<ref>{{cite web|title=Protein sequence of human MYL4 (Uniprot ID: P12829)|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P12829|website=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)|accessdate=30 June 2015}}</ref> ALC-1 is expressed in fetal [[Ventricle (heart)|cardiac ventricular]] and fetal [[skeletal muscle]], as well as fetal and adult [[Atrium (heart)|cardiac atrial]] tissue.<ref name="Kurabayashi_1988"/> ALC-1 binds the neck region of muscle [[MYH7|myosin]] in adult [[atrium (heart)|atria]]. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.<ref>{{cite journal | vauthors = Zimmermann K, Kautz S, Hajdu G, Winter C, Whalen RG, Starzinski-Powitz A | title = Heterogenic mRNAs with an identical protein-coding region of the human embryonic myosin alkali light chain in skeletal muscle cells | journal = Journal of Molecular Biology | volume = 211 | issue = 3 | pages = 505–13 | date = February 1990 | pmid = 2308163 | doi = 10.1016/0022-2836(90)90261-J }}</ref> Relative to ventricular essential light chain [[MYL6|VLC-1]], ALC-1 has an additional ~40 amino-acid [[N-terminus|N-terminal]] region that contains four to eleven residues that are critical for binding [[actin]] and modulating [[MYH7|myosin]] kinetics.<ref name = "Timson_1998">{{cite journal | vauthors = Timson DJ, Trayer HR, Trayer IP | title = The N-terminus of A1-type myosin essential light chains binds actin and modulates myosin motor function | journal = European Journal of Biochemistry / FEBS | volume = 255 | issue = 3 | pages = 654–62 | date = August 1998 | pmid = 9738905 | doi=10.1046/j.1432-1327.1998.2550654.x}}</ref><ref name = "Timson_1999">{{cite journal | vauthors = Timson DJ, Trayer HR, Smith KJ, Trayer IP | title = Size and charge requirements for kinetic modulation and actin binding by alkali 1-type myosin essential light chains | journal = The Journal of Biological Chemistry | volume = 274 | issue = 26 | pages = 18271–7 | date = June 1999 | pmid = 10373429 | doi=10.1074/jbc.274.26.18271}}</ref>
| image = 
| image_source = 
| PDB =
| Name = Myosin, light chain 4, alkali; atrial, embryonic
| HGNCid = 7585
| Symbol = MYL4
| AltSymbols =; GT1; ALC1; AMLC; PRO1957
| OMIM = 160770
| ECnumber = 
| Homologene = 20558
| MGIid = 97267
| GeneAtlas_image1 = PBB_GE_MYL4_210395_x_at_tn.png
| GeneAtlas_image2 = PBB_GE_MYL4_210088_x_at_tn.png
| GeneAtlas_image3 = PBB_GE_MYL4_216054_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003774 |text = motor activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0008307 |text = structural constituent of muscle}}
| Component = {{GNF_GO|id=GO:0005859 |text = muscle myosin complex}} {{GNF_GO|id=GO:0016459 |text = myosin complex}}
| Process = {{GNF_GO|id=GO:0006941 |text = striated muscle contraction}} {{GNF_GO|id=GO:0007517 |text = muscle development}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4635
    | Hs_Ensembl = ENSG00000198336
    | Hs_RefseqProtein = NP_001002841
    | Hs_RefseqmRNA = NM_001002841
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 42641427
    | Hs_GenLoc_end = 42656043
    | Hs_Uniprot = P12829
    | Mm_EntrezGene = 17896
    | Mm_Ensembl = ENSMUSG00000061086
    | Mm_RefseqmRNA = NM_010858
    | Mm_RefseqProtein = NP_034988
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 104366753
    | Mm_GenLoc_end = 104403309
    | Mm_Uniprot = Q9CZ19
  }}
}}
'''Myosin, light chain 4, alkali; atrial, embryonic''', also known as '''MYL4''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4635| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
ALC-1 is expressed very early in [[skeletal muscle]] and [[cardiac muscle]] development; two [[E-box]]es and CArG box in the ''MYL4'' promoter region regulate transcription.<ref>{{cite journal | vauthors = Catala F, Wanner R, Barton P, Cohen A, Wright W, Buckingham M | title = 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 | journal = Molecular and Cellular Biology | volume = 15 | issue = 8 | pages = 4585–96 | date = August 1995 | pmid = 7623850 | doi=10.1128/mcb.15.8.4585 | pmc=230699}}</ref> ALC-1 expression in cardiac [[ventricle (heart)|ventricles]] decreases in early postnatal development, but is highly expressed in [[atrium (heart)|atria]] throughout all of adulthood.<ref name = "Auckland_1986">{{cite journal | vauthors = Auckland LM, Lambert SJ, Cummins P | title = Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot | journal = Cardiovascular Research | volume = 20 | issue = 11 | pages = 828–36 | date = November 1986 | pmid = 3621284 | doi=10.1093/cvr/20.11.828}}</ref><ref>{{cite journal | vauthors = Cummins P, Lambert SJ | title = Myosin transitions in the bovine and human heart. A developmental and anatomical study of heavy and light chain subunits in the atrium and ventricle | journal = Circulation Research | volume = 58 | issue = 6 | pages = 846–58 | date = June 1986 | pmid = 3719931 | doi=10.1161/01.res.58.6.846}}</ref> Normal atrial function is essential for embryogenesis, as inactivation of the ''MYL7'' gene was embryonic lethal at ED10.5-11.5.<ref>{{cite journal | vauthors = Huang C, Sheikh F, Hollander M, Cai C, Becker D, Chu PH, Evans S, Chen J | title = Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis | journal = Development | volume = 130 | issue = 24 | pages = 6111–9 | date = December 2003 | pmid = 14573518 | doi = 10.1242/dev.00831 }}</ref>
| section_title =  
| summary_text = Myosin is a hexameric ATPase cellular motor protein. It is composed of two myosin heavy chains, two nonphosphorylatable myosin alkali light chains, and two phosphorylatable myosin regulatory light chains. This gene encodes a myosin alkali light chain that is found in embryonic muscle and adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: MYL4 myosin, light chain 4, alkali; atrial, embryonic| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4635| accessdate = }}</ref>
}}


==References==
Evidence of ALC-1 isoform expression on contractile mechanics of [[sarcomere]]s came from experiments studying fibers from patients expressing a higher level of ALC-1 relative to [[MYL6|VLC-1]] in cardiac left [[ventricle (heart)|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]].<ref name = "Morano_1996">{{cite journal | vauthors = Morano M, Zacharzowski U, Maier M, Lange PE, Alexi-Meskishvili V, Haase H, Morano I | title = Regulation of human heart contractility by essential myosin light chain isoforms | journal = The Journal of Clinical Investigation | volume = 98 | issue = 2 | pages = 467–73 | date = July 1996 | pmid = 8755658 | doi = 10.1172/JCI118813 | pmc=507451}}</ref> Further biochemical studies unveiled a weaker binding of the [[Alanine]]-[[Proline]]-rich [[N-terminus]] of ALC-1<ref name = "Timson_1998"/> to the [[C-terminus]] of [[actin]] relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics.<ref>{{cite journal | vauthors = Morano I, Haase H | title = Different actin affinities of human cardiac essential myosin light chain isoforms | journal = FEBS Letters | volume = 408 | issue = 1 | pages = 71–4 | date = May 1997 | pmid = 9180271 | doi=10.1016/s0014-5793(97)00390-6}}</ref><ref name = "Petzhold_2014">{{cite journal | vauthors = Petzhold D, Simsek B, Meißner R, Mahmoodzadeh S, Morano I | title = Distinct interactions between actin and essential myosin light chain isoforms | journal = Biochemical and Biophysical Research Communications | volume = 449 | issue = 3 | pages = 284–8 | date = July 2014 | pmid = 24857983 | doi = 10.1016/j.bbrc.2014.05.040 }}</ref> The importance of this region has however raised skepticism.<ref>{{cite journal | vauthors = Sanbe A, Gulick J, Fewell J, Robbins J | title = Examining the in vivo role of the amino terminus of the essential myosin light chain | journal = The Journal of Biological Chemistry | volume = 276 | issue = 35 | pages = 32682–6 | date = August 2001 | pmid = 11432848 | doi = 10.1074/jbc.M009975200 }}</ref> 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 [[cardiac cycle#diastole|relaxation]] in whole heart experiments.<ref>{{cite journal | vauthors = Fewell JG, Hewett TE, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J | title = Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice | journal = The Journal of Clinical Investigation | volume = 101 | issue = 12 | pages = 2630–9 | date = June 1998 | pmid = 9637696 | doi = 10.1172/JCI2825 | pmc=508853}}</ref> These studies were supported by further studies in transgenic rats overexpressing ALC-1 which showed enhanced rates of [[Muscle contraction|contraction]] and [[cardiac cycle#diastole|relaxation]], as well as left [[Ventricle (heart)|ventricular]] developed pressure in [[Langendorff heart]] preparations.<ref>{{cite journal | vauthors = Abdelaziz AI, Segaric J, Bartsch H, Petzhold D, Schlegel WP, Kott M, Seefeldt I, Klose J, Bader M, Haase H, Morano I | title = Functional characterization of the human atrial essential myosin light chain (hALC-1) in a transgenic rat model | journal = Journal of Molecular Medicine | volume = 82 | issue = 4 | pages = 265–74 | date = April 2004 | pmid = 14985854 | doi = 10.1007/s00109-004-0525-4 }}</ref> Importantly, overexpression of ALC-1 was shown to attenuate [[heart failure]] in pressure-overloaded animals, by enhancing left [[Ventricle (heart)|ventricular]] developed pressure, maximal velocity of pressure development and relaxation.<ref>{{cite journal | vauthors = Abdelaziz AI, Pagel I, Schlegel WP, Kott M, Monti J, Haase H, Morano I | title = Human atrial myosin light chain 1 expression attenuates heart failure | journal = Advances in Experimental Medicine and Biology | volume = 565 | pages = 283–92; discussion 92, 405–15 | date = 2005 | pmid = 16106982 | doi = 10.1007/0-387-24990-7_21 }}</ref>
{{reflist|2}}
 
==Further reading==
==Clinical significance==
{{refbegin | 2}}
''MYL4'' expression in [[Ventricle (heart)|ventricular]] [[myocardium]] has shown to abnormally persist in [[neonate]]s up through adulthood in patients with the [[congenital heart disease]], [[tetralogy of Fallot]].<ref name = "Auckland_1986"/> Altered ALC-1 expression is also altered in other [[congenital heart disease]]s, [[Double outlet right ventricle]] and [[ventricular septal defect#2. Type 1 (Subarterial) (Supracristal) (Conal septal defect) (Infundibular)|infundibular pulmonary stenosis]].<ref name = "Morano_1996"/>  Moreover, in patients with [[aortic stenosis]] or [[aortic insufficiency]], ALC-1 expression in left [[Ventricle (heart)|ventricle]]s was elevated, and following valve replacement decreased to lower levels; ALC-1 expression also correlated with left [[Ventricle (heart)|ventricular]] systolic pressure.<ref>{{cite journal | vauthors = Sütsch G, Brunner UT, von Schulthess C, Hirzel HO, Hess OM, Turina M, Krayenbuehl HP, Schaub MC | title = Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement | journal = Circulation Research | volume = 70 | issue = 5 | pages = 1035–43 | date = May 1992 | pmid = 1533180 | doi=10.1161/01.res.70.5.1035}}</ref>
{{PBB_Further_reading
 
| citations =  
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 [[Ventricle (heart)|ventricular]] dP/dtmax and [[ejection fraction]].<ref>{{cite journal | vauthors = Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO | title = Myosin isoenzymes in human hypertrophic hearts. Shift in atrial myosin heavy chains and in ventricular myosin light chains | journal = European Heart Journal | volume = 5 Suppl F | pages = 85–93 | date = December 1984 | pmid = 6241906 | doi=10.1093/eurheartj/5.suppl_f.85}}</ref><ref>{{cite journal | vauthors = Schaub MC, Hefti MA, Zuellig RA, Morano I | title = Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms | journal = Cardiovascular Research | volume = 37 | issue = 2 | pages = 381–404 | date = February 1998 | pmid = 9614495 | doi=10.1016/s0008-6363(97)00258-7}}</ref><ref>{{cite journal | vauthors = Morano I, Hädicke K, Haase H, Böhm M, Erdmann E, Schaub MC | title = Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart | journal = Journal of Molecular and Cellular Cardiology | volume = 29 | issue = 4 | pages = 1177–87 | date = April 1997 | pmid = 9160869 | doi = 10.1006/jmcc.1996.0353 }}</ref><ref>{{cite journal | vauthors = Ritter O, Luther HP, Haase H, Baltas LG, Baumann G, Schulte HD, Morano I | title = 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 = Journal of Molecular Medicine | volume = 77 | issue = 9 | pages = 677–85 | date = September 1999 | pmid = 10569205 | doi=10.1007/s001099900030}}</ref><ref>{{cite journal | vauthors = Ritter O, Bottez N, Burkard N, Schulte HD, Neyses L | title = A molecular mechanism improving the contractile state in human myocardial hypertrophy | journal = Experimental and Clinical Cardiology | volume = 7 | issue = 2–3 | pages = 151–7 | date = 2002 | pmid = 19649240 | pmc=2719172}}</ref>
*{{cite journal | author=Rotter M, Zimmerman K, Poustka A, ''et al.'' |title=The human embryonic myosin alkali light chain gene: use of alternative promoters and 3' non-coding regions. |journal=Nucleic Acids Res. |volume=19 |issue= 7 |pages= 1497-504 |year= 1991 |pmid= 2027757 |doi= }}
 
*{{cite journal  | author=Seharaseyon J, Bober E, Hsieh CL, ''et al.'' |title=Human embryonic/atrial myosin alkali light chain gene: characterization, sequence, and chromosomal location. |journal=Genomics |volume=7 |issue= 2 |pages= 289-93 |year= 1990 |pmid= 2129532 |doi= }}
== Interactions ==
*{{cite journal | author=Zimmermann K, Kautz S, Hajdu G, ''et al.'' |title=Heterogenic mRNAs with an identical protein-coding region of the human embryonic myosin alkali light chain in skeletal muscle cells. |journal=J. Mol. Biol. |volume=211 |issue= 3 |pages= 505-13 |year= 1990 |pmid= 2308163 |doi= }}
ALC-1 [[protein-protein interaction|interacts]] with:
*{{cite journal | author=Seidel U, Bober E, Winter B, ''et al.'' |title=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. |journal=Gene |volume=66 |issue= 1 |pages= 135-46 |year= 1988 |pmid= 2458299 |doi= }}
*[[ACTC1]]<ref name = "Timson_1998"/><ref name = "Timson_1999"/><ref name = "Petzhold_2014"/>
*{{cite journal  | author=Arnold HH, Lohse P, Seidel U, Bober E |title=A novel human myosin alkali light chain is developmentally regulated. Expression in fetal cardiac and skeletal muscle and in adult atria. |journal=Eur. J. Biochem. |volume=178 |issue= 1 |pages= 53-60 |year= 1989 |pmid= 2849544 |doi= }}
*[[MYH7]]<ref>{{cite journal | vauthors = Yang JH, Zheng DD, Dong NZ, Yang XJ, Song JP, Jiang TB, Cheng XJ, Li HX, Zhou BY, Zhao CM, Jiang WP | title = Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy | journal = Chinese Medical Journal | volume = 119 | issue = 21 | pages = 1785–9 | date = November 2006 | pmid = 17097032 }}</ref><ref>{{cite journal | vauthors = Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM | title = Three-dimensional structure of myosin subfragment-1: a molecular motor | journal = Science | volume = 261 | issue = 5117 | pages = 50–8 | date = July 1993 | pmid = 8316857 | doi=10.1126/science.8316857}}</ref><ref>{{cite journal | vauthors = Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I | title = Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity | journal = Cardiovascular Research | volume = 90 | issue = 3 | pages = 513–20 | date = June 2011 | pmid = 21262909 | doi = 10.1093/cvr/cvr026 }}</ref>
*{{cite journal | author=Kurabayashi M, Komuro I, Tsuchimochi H, ''et al.'' |title=Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones. |journal=J. Biol. Chem. |volume=263 |issue= 27 |pages= 13930-6 |year= 1988 |pmid= 3417683 |doi= }}
 
*{{cite journal | author=Strohman RC, Micou-Eastwood J, Glass CA, Matsuda R |title=Human fetal muscle and cultured myotubes derived from it contain a fetal-specific myosin light chain. |journal=Science |volume=221 |issue= 4614 |pages= 955-7 |year= 1983 |pmid= 6879193 |doi= }}
== References ==
*{{cite journal  | author=Timson DJ, Trayer IP |title=The rôle of the proline-rich region in A1-type myosin essential light chains: implications for information transmission in the actomyosin complex. |journal=FEBS Lett. |volume=400 |issue= 1 |pages= 31-6 |year= 1997 |pmid= 9000508 |doi=  }}
{{reflist|33em}}
*{{cite journal | author=Timson DJ, Trayer HR, Trayer IP |title=The N-terminus of A1-type myosin essential light chains binds actin and modulates myosin motor function. |journal=Eur. J. Biochem. |volume=255 |issue= 3 |pages= 654-62 |year= 1998 |pmid= 9738905 |doi= }}
 
*{{cite journal  | author=Timson DJ, Trayer HR, Smith KJ, Trayer IP |title=Size and charge requirements for kinetic modulation and actin binding by alkali 1-type myosin essential light chains. |journal=J. Biol. Chem. |volume=274 |issue= 26 |pages= 18271-7 |year= 1999 |pmid= 10373429 |doi= }}
== Further reading ==
*{{cite journal | author=Morano I |title=Tuning the human heart molecular motors by myosin light chains. |journal=J. Mol. Med. |volume=77 |issue= 7 |pages= 544-55 |year= 1999 |pmid= 10494800 |doi= }}
{{refbegin|33em}}
*{{cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi= }}
* {{cite journal | vauthors = Rotter M, Zimmerman K, Poustka A, Soussi-Yanicostas N, Starzinski-Powitz A | title = The human embryonic myosin alkali light chain gene: use of alternative promoters and 3' non-coding regions | journal = Nucleic Acids Research | volume = 19 | issue = 7 | pages = 1497–504 | date = April 1991 | pmid = 2027757 | pmc = 333907 | doi = 10.1093/nar/19.7.1497 }}
*{{cite journal | author=Arrell DK, Neverova I, Fraser H, ''et al.'' |title=Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1. |journal=Circ. Res. |volume=89 |issue= 6 |pages= 480-7 |year= 2001 |pmid= 11557734 |doi= }}
* {{cite journal | vauthors = Seharaseyon J, Bober E, Hsieh CL, Fodor WL, Francke U, Arnold HH, Vanin EF | title = Human embryonic/atrial myosin alkali light chain gene: characterization, sequence, and chromosomal location | journal = Genomics | volume = 7 | issue = 2 | pages = 289–93 | date = June 1990 | pmid = 2129532 | doi = 10.1016/0888-7543(90)90554-8 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Seidel U, Bober E, Winter B, Lenz S, Lohse P, Goedde HW, Grzeschik KH, Arnold HH | title = 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 | journal = Gene | volume = 66 | issue = 1 | pages = 135–46 | date = June 1988 | pmid = 2458299 | doi = 10.1016/0378-1119(88)90231-4 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
* {{cite journal | vauthors = Arnold HH, Lohse P, Seidel U, Bober E | title = A novel human myosin alkali light chain is developmentally regulated. Expression in fetal cardiac and skeletal muscle and in adult atria | journal = European Journal of Biochemistry / FEBS | volume = 178 | issue = 1 | pages = 53–60 | date = December 1988 | pmid = 2849544 | doi = 10.1111/j.1432-1033.1988.tb14428.x }}
*{{cite journal | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
* {{cite journal | vauthors = Strohman RC, Micou-Eastwood J, Glass CA, Matsuda R | title = Human fetal muscle and cultured myotubes derived from it contain a fetal-specific myosin light chain | journal = Science | volume = 221 | issue = 4614 | pages = 955–7 | date = September 1983 | pmid = 6879193 | doi = 10.1126/science.6879193 }}
*{{cite journal | author=Abdelaziz AI, Pagel I, Schlegel WP, ''et al.'' |title=Human atrial myosin light chain 1 expression attenuates heart failure. |journal=Adv. Exp. Med. Biol. |volume=565 |issue= |pages= 283-92; discussion 92, 405-15 |year= 2006 |pmid= 16106982 |doi= }}
* {{cite journal | vauthors = Timson DJ, Trayer IP | title = The rôle of the proline-rich region in A1-type myosin essential light chains: implications for information transmission in the actomyosin complex | journal = FEBS Letters | volume = 400 | issue = 1 | pages = 31–6 | date = Jan 1997 | pmid = 9000508 | doi = 10.1016/S0014-5793(96)01314-2 }}
*{{cite journal | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
* {{cite journal | vauthors = Morano I | title = Tuning the human heart molecular motors by myosin light chains | journal = Journal of Molecular Medicine | volume = 77 | issue = 7 | pages = 544–55 | date = July 1999 | pmid = 10494800 | doi = 10.1007/s001099900031 }}
}}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal | vauthors = Arrell DK, Neverova I, Fraser H, Marbán E, Van Eyk JE | title = Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1 | journal = Circulation Research | volume = 89 | issue = 6 | pages = 480–7 | date = September 2001 | pmid = 11557734 | doi = 10.1161/hh1801.097240 }}
* {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
* {{cite journal | vauthors = 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 | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415-8 | date = Jan 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
{{refend}}
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Latest revision as of 18:34, 17 October 2018

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Orthologs
SpeciesHumanMouse
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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.

Further reading

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