MYL7

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

Structure
Human ALC-2 is_associated_with::protein has a molecular weight of 19.4 kDa and is composed of 175 amino acids. ALC-2 is an is_associated_with::EF hand protein that binds to the neck region of alpha myosin heavy chain. 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), is_associated_with::Serine-15 and is_associated_with::Serine/is_associated_with::Asparagine-14.

Function
ALC-2 expression has proven to be a useful marker of is_associated_with::cardiac muscle chamber distinction, development and differentiation. 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 is_associated_with::aorta and undetectable in ventricles, is_associated_with::skeletal muscle, is_associated_with::uterus, and is_associated_with::liver. This atrial patterning occurs prior to septation. Expression of ALC-2 has been shown to correlate with expression of alpha-myosin heavy chain in cardiac atria of non-human primates.

ALC-2 and VLC-2 appear to function in the stabilization of thick filaments and regulation of is_associated_with::contractility in the vertebrate heart. 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 is_associated_with::myocytes that contract and relax more forcefully and quickly, resulting in atrial is_associated_with::cardiomyocytes that behave as ventricular is_associated_with::cardiomyocytes.

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 is_associated_with::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 is_associated_with::cardiac hypertrophy. Moreover, in a porcine model of is_associated_with::atrial fibrillation, VLC-2 is_associated_with::mRNA expression showed the greatest change, being upregulated 9.4-fold and 7.3-fold in left and right atria, respectively. In a porcine model of left atrial remodeling following is_associated_with::mitral regurgitation, VLC-2 was shown to be upregulated.

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

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

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

Interactions
ALC-2 is shown to interact with:
 * is_associated_with::MYH6