Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''MYL7''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. ALC-2 expression is restricted to

cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...

atria in healthy individuals, where it functions to modulate cardiac development and

contractility Contractility refers to the ability for self-contraction, especially of the muscles or similar active biological tissue *Contractile ring in cytokinesis *Contractile vacuole *Muscle contraction **Myocardial contractility *See contractile cell for ...

. In human diseases, including hypertrophic cardiomyopathy,

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...

, ischemic cardiomyopathy and others, ALC-2 expression is altered.

Structure

Human ALC-2

has a molecular weight of 19.4 kDa and is composed of 175 amino acids. ALC-2 is an

EF hand The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins. The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, i ...

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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and at the regulatory phosphorylation site(s), Serine-15 and Serine/

Asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

-14.

Function

ALC-2 expression has proven to be a useful marker of

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 The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

-specific throughout embryonic days 8-16, and from day 12 and on is restricted to atria, showing very low levels in

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...

and undetectable in ventricles, skeletal muscle,

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

, and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. This

atrial The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves. There are two at ...

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 Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the ''contractile proteins'' and titin is an elastic protein. The myofilaments act toget ...

and regulation of

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

myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

that

contract A contract is a legally enforceable agreement between two or more parties that creates, defines, and governs mutual rights and obligations between them. A contract typically involves the transfer of goods, services, money, or a promise to tr ...

and

relax Relax may refer to: Aviation * Roland Z-120 Relax, a German ultralight aircraft design for the 120 kg class Music Albums * ''Relax'' (Blank & Jones album), 2003 * ''Relax'' (Das Racist album), 2011 Songs * "Relax" (song), a 1983 song by Fran ...

more forcefully and quickly, resulting in

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

that behave as ventricular

. 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 In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

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. Moreover, in a porcine model of atrial fibrillation, VLC-2

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

remodeling following mitral regurgitation, VLC-2 was shown to be upregulated. Human ALC-2 is phosphorylated at its N-terminus at Serine-15 by a cardiac-specific

myosin light chain kinase Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II. General structural features While there ar ...

; ALC-2 has a serine at position 14, which is an

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. Alpha(1)-adrenergic stimulation by

phenylephrine Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...

muscle strips showed an 80% increase in ALC-2 phosphorylation coordinate with enhanced contractile force, which was inhibited by both Rho kinase and

inhibition. In a canine model of atrial fibrillation, decreased

was associated with decreased ALC-2 and myosin binding protein C phosphorylation. Moreover, the slow force response induced by stretch in human

muscle was shown to be modulated by enhanced phosphorylation of ALC-2 by

Clinical Significance

Patients with hypertrophic cardiomyopathy shown an increased expression of ALC-2 in whole heart tissue. In patients with mitral valve disease, ischemic cardiomyopathy,

coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

and pressure overload-induced cardiac hypertrophy, ALC-2 was shown to be replaced with VLC-2 in cardiac atria; in

, this change was concomitant with enhanced sensitivity of

fibers to

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...

. In patients with congenital

atrial septal defect Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

carrying a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

Ile820 Asn 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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

MYH6 Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the ''MYH6'' gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominan ...

Structure

Function

Clinical Significance

Interactions

References

Further reading