MYL4

Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a is_associated_with::protein that in humans is encoded by the MYL4 is_associated_with::gene. ALC-1 is expressed in fetal cardiac ventricular and fetal is_associated_with::skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular is_associated_with::myocardium in various is_associated_with::cardiac muscle diseases, including is_associated_with::hypertrophic cardiomyopathy, is_associated_with::dilated cardiomyopathy, is_associated_with::ischemic cardiomyopathy and is_associated_with::congenital heart diseases.

Structure
ALC-1 is a 21.6 kDa protein composed of 197 amino acids. ALC-1 is expressed in fetal cardiac ventricular and fetal is_associated_with::skeletal muscle, as well as fetal and adult cardiac atrial tissue. 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. 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 is_associated_with::actin and modulating myosin kinetics.

Function
ALC-1 is expressed very early in is_associated_with::skeletal muscle and is_associated_with::cardiac muscle development; two is_associated_with::E-boxes and CArG box in the MYL4 promoter region regulate transcription. ALC-1 expression in cardiac ventricles decreases in early postnatal development, but is highly expressed in atria throughout all of adulthood. ALC-1 expression and normal atrial function are essential for embryogenesis, as inactivation of the MYL4 gene was embryonic lethal at ED10.5-11.5.

Evidence of ALC-1 isoform expression on contractile mechanics of is_associated_with::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 is_associated_with::contractility. Further biochemical studies unveiled a weaker binding of the is_associated_with::Alanine-is_associated_with::Proline-rich is_associated_with::N-terminus of ALC-1 to the is_associated_with::C-terminus of is_associated_with::actin relative to VLC-1, which may explain the mechanism underlying the differences in cycling kinetics. The importance of this region has however raised skepticism. 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 is_associated_with::in vitro motility assay, as well as enhanced is_associated_with::contractility and relaxation in whole heart experiments. 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 is_associated_with::Langendorff heart preparations. Importantly, overexpression of ALC-1 was shown to attenuate is_associated_with::heart failure in pressure-overloaded animals, by enhancing left ventricular developed pressure, maximal velocity of pressure development and relaxation.

Clinical Significance
MYL4 expression in venticular is_associated_with::myocardium has shown to abnormally persist in is_associated_with::neonates up through adulthood in patients with the is_associated_with::congenital heart disease, is_associated_with::tetralogy of Fallot. Altered ALC-1 expression is also altered in other is_associated_with::congenital heart diseases, is_associated_with::Double outlet right ventricle and infundibular pulmonary stenosis. Moreover, in patients with is_associated_with::aortic stenosis or is_associated_with::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.

Additionally, in patients with is_associated_with::ischemic cardiomyopathy, is_associated_with::dilated cardiomyopathy and is_associated_with::hypertrophic cardiomyopathy, ALC-1 protein expression is shown to be reactivated, and ALC-1 expression correlates with is_associated_with::calcium sensitivity of is_associated_with::myofilament proteins in skinned fiber preparations, as well as ventricular dP/dtmax and is_associated_with::ejection fraction.

Interactions
ALC-1 interacts with:
 * is_associated_with::ACTC1
 * is_associated_with::MYH7