# MYL3

## Overview
The MYL3 gene encodes the myosin light chain 3 (MLC3), a protein that plays a pivotal role in cardiac muscle contraction. MLC3 is categorized as an essential light chain (ELC) and is part of the myosin complex, which is crucial for the structural stability and function of the myosin motor in cardiac muscle fibers. This protein is predominantly expressed in the ventricles of the heart, where it interacts with the myosin heavy chain (MHC) and actin, influencing muscle contraction and force production (Hernandez2007Myosin; Sitbon2019Insights). The MYL3 gene is also involved in the regulation of cardiac muscle contraction through its role in the calcium-dependent mechanisms that govern the heart's pumping efficiency (Hernandez2007Myosin; Sitbon2019Insights). Mutations in MYL3 have been linked to various cardiomyopathies, including hypertrophic and dilated cardiomyopathy, highlighting its clinical significance in cardiovascular health (Mavilakandy2022Mutation; Osborn2021Autosomal).

## Structure
The MYL3 gene encodes the essential light chain (ELC) of cardiac myosin, which plays a crucial role in muscle contraction. The ELC is part of the EF-hand Ca2+ binding protein family, although it has lost the ability to bind calcium in humans (Sitbon2019Insights; Huang2015Molecular). The N-terminal extension of the ELC is significant for actin-myosin interaction, acting as a bridge between the myosin head and actin, which influences force production and muscle contraction (Sitbon2019Insights). This region is crucial for proper myosin head orientation and muscle function, as demonstrated by studies on mice expressing a truncated ELC (Muthu2011Structural).

The C-terminal region of the ELC interacts with the myosin heavy chain (MHC) and possibly with the regulatory light chain (RLC) (Sitbon2019Insights). Phosphorylation sites, such as Ser195, have been identified, although no phosphorylation of ventricular or atrial ELC isoforms was found in human or swine myocardium (Sitbon2019Insights; Huang2015Molecular). The MYL3 gene also encodes different isoforms, including ventricular and slow-skeletal ELC, with variations in their N-terminal regions (Sitbon2019Insights).

## Function
The MYL3 gene encodes the ventricular essential light chain (ELC) of myosin, which plays a critical role in cardiac muscle contraction. In healthy human cells, MYL3 is predominantly expressed in the ventricles of the heart, where it contributes to the structural stability of the myosin head's lever arm domain. This stability is crucial for the proper function of the myosin motor, which is responsible for muscle contraction (Hernandez2007Myosin; Petzhold2011Human).

The ELC encoded by MYL3 interacts with actin, influencing myosin's affinity for actin, ATPase activity, and cross-bridge cycling kinetics. These interactions are essential for the regulation of muscle contraction and force production in cardiac muscle (Sitbon2019Insights; Hernandez2007Myosin). The N-terminal extension of the ELC is particularly important for actin-myosin interaction, affecting the force production and efficiency of muscle contraction (Sitbon2019Insights).

MYL3 is also involved in the calcium-dependent regulation of cardiac muscle contraction, contributing to the heart's pumping efficiency and overall cardiovascular function. The expression of MYL3 is tissue-specific, with its isoforms being expressed in slow skeletal muscle and myocardium, highlighting its role in maintaining normal muscle function (Hernandez2007Myosin; Sitbon2019Insights).

## Clinical Significance
Mutations in the MYL3 gene are associated with various forms of cardiomyopathy, a group of diseases affecting the heart muscle. One notable condition linked to MYL3 mutations is autosomal recessive cardiomyopathy, characterized by mid-cavitary left ventricular hypertrophy and restrictive physiology. This condition is often caused by a homozygous Glu143Lys substitution in the MYL3 gene, leading to severe cardiomyopathy in affected individuals, while heterozygous carriers typically maintain normal cardiac function (Olson2002Myosin).

MYL3 mutations are also implicated in hypertrophic cardiomyopathy (HCM), a condition marked by thickened heart muscle. For instance, a heterozygous missense mutation resulting in a Glu152Lys substitution has been associated with mid-ventricular obstructive HCM, which can lead to complications such as left ventricular apical aneurysm and increased risk of sudden cardiac death (Mavilakandy2022Mutation).

Additionally, MYL3 variants have been linked to dilated cardiomyopathy (DCM) and sudden cardiac death, with certain mutations causing loss-of-function effects that impair cardiac function. These mutations can result in severe phenotypes and early onset of symptoms, including sudden cardiac death in homozygous individuals (Osborn2021Autosomal).

## Interactions
The MYL3 gene encodes the myosin essential light chain (ELC), which plays a critical role in muscle contraction by interacting with various proteins. MYL3 is involved in the formation of the myosin complex, where it binds to the myosin heavy chain (MHC), stabilizing the α-helix of the regulatory domain of the myosin head. This interaction is crucial for the structural stability of the myosin cross-bridge and effective force generation during muscle contraction (Huang2015Molecular; Yampolskaya2022Properties).

The ELC encoded by MYL3 also interacts with actin, a key component of the thin filament in muscle fibers. This interaction is essential for modulating muscle contractile activity, as the ELC can influence the actin-myosin interaction, affecting force production and muscle contraction (Petzhold2014Distinct; Sitbon2019Insights). The N-terminal region of the ELC is particularly important for its interaction with actin, potentially altering force development (Sitbon2019Insights).

Mutations in MYL3, such as E56G and M149V, can disrupt these interactions, leading to altered myosin function and are associated with conditions like hypertrophic cardiomyopathy (Hernandez2007Myosin; Yampolskaya2022Properties). These mutations can affect the affinity of ELC for MHC and actin, impacting the contractile properties of cardiac muscle (Yampolskaya2022Properties).


## References


[1. (Olson2002Myosin) Timothy M. Olson, Margaret L. Karst, Frank G. Whitby, and David J. Driscoll. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation, 105(20):2337–2340, May 2002. URL: http://dx.doi.org/10.1161/01.cir.0000018444.47798.94, doi:10.1161/01.cir.0000018444.47798.94. This article has 81 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1161/01.cir.0000018444.47798.94)

[2. (Huang2015Molecular) Wenrui Huang and Danuta Szczesna-Cordary. Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations. Journal of Muscle Research and Cell Motility, 36(6):433–445, September 2015. URL: http://dx.doi.org/10.1007/s10974-015-9423-3, doi:10.1007/s10974-015-9423-3. This article has 32 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10974-015-9423-3)

[3. (Hernandez2007Myosin) Olga M. Hernandez, Michelle Jones, Georgianna Guzman, and Danuta Szczesna-Cordary. Myosin essential light chain in health and disease. American Journal of Physiology-Heart and Circulatory Physiology, 292(4):H1643–H1654, April 2007. URL: http://dx.doi.org/10.1152/ajpheart.00931.2006, doi:10.1152/ajpheart.00931.2006. This article has 95 citations.](https://doi.org/10.1152/ajpheart.00931.2006)

[4. (Sitbon2019Insights) Yoel H. Sitbon, Sunil Yadav, Katarzyna Kazmierczak, and Danuta Szczesna‐Cordary. Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease. Journal of Muscle Research and Cell Motility, 41(4):313–327, May 2019. URL: http://dx.doi.org/10.1007/s10974-019-09517-x, doi:10.1007/s10974-019-09517-x. This article has 43 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10974-019-09517-x)

[5. (Mavilakandy2022Mutation) Akash Mavilakandy and Hisham Ahamed. Mutation of themyl3gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy. BMJ Case Reports, 15(3):e244573, March 2022. URL: http://dx.doi.org/10.1136/bcr-2021-244573, doi:10.1136/bcr-2021-244573. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1136/bcr-2021-244573)

[6. (Petzhold2014Distinct) Daria Petzhold, Burcu Simsek, Ralf Meißner, Shokoufeh Mahmoodzadeh, and Ingo Morano. Distinct interactions between actin and essential myosin light chain isoforms. Biochemical and Biophysical Research Communications, 449(3):284–288, July 2014. URL: http://dx.doi.org/10.1016/j.bbrc.2014.05.040, doi:10.1016/j.bbrc.2014.05.040. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2014.05.040)

[7. (Yampolskaya2022Properties) Daria S. Yampolskaya, Galina V. Kopylova, Daniil V. Shchepkin, Sergey Y. Bershitsky, Alexander M. Matyushenko, and Dmitrii I. Levitsky. Properties of cardiac myosin with cardiomyopathic mutations in essential light chains. Biochemistry (Moscow), 87(11):1260–1267, November 2022. URL: http://dx.doi.org/10.1134/S0006297922110050, doi:10.1134/s0006297922110050. This article has 0 citations.](https://doi.org/10.1134/S0006297922110050)

[8. (Muthu2011Structural) Priya Muthu, Li Wang, Chen‐Ching Yuan, Katarzyna Kazmierczak, Wenrui Huang, Olga M. Hernandez, Masataka Kawai, Thomas C. Irving, and Danuta Szczesna‐Cordary. Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. The FASEB Journal, 25(12):4394–4405, September 2011. URL: http://dx.doi.org/10.1096/fj.11-191973, doi:10.1096/fj.11-191973. This article has 46 citations.](https://doi.org/10.1096/fj.11-191973)

[9. (Petzhold2011Human) D. Petzhold, J. Lossie, S. Keller, S. Werner, H. Haase, and I. Morano. Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. Cardiovascular Research, 90(3):513–520, January 2011. URL: http://dx.doi.org/10.1093/cvr/cvr026, doi:10.1093/cvr/cvr026. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/cvr/cvr026)

[10. (Osborn2021Autosomal) Daniel Peter Sayer Osborn, Leila Emrahi, Joshua Clayton, Mehrnoush Toufan Tabrizi, Alex Yui Bong Wan, Reza Maroofian, Mohammad Yazdchi, Michael Leon Enrique Garcia, Hamid Galehdari, Camila Hesse, Gholamreza Shariati, Neda Mazaheri, Alireza Sedaghat, Hayley Goullée, Nigel Laing, Yalda Jamshidi, and Homa Tajsharghi. Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in myl3. Genetics in Medicine, 23(4):787–792, April 2021. URL: http://dx.doi.org/10.1038/s41436-020-01028-2, doi:10.1038/s41436-020-01028-2. This article has 20 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41436-020-01028-2)