# MYOM1

## Overview
The MYOM1 gene encodes the protein myomesin 1, a crucial structural component of the M-band in striated muscle sarcomeres. Myomesin 1 is categorized as a structural protein, characterized by its modular architecture comprising immunoglobulin-like and fibronectin type III domains. This protein plays a pivotal role in maintaining the structural integrity and elasticity of muscle tissues by cross-linking myosin filaments and interacting with other sarcomeric proteins such as titin and obscurin. These interactions are essential for the formation and stabilization of the M-band, contributing to the alignment and centering of the A-band during muscle contraction and relaxation (Lamber2022The; Fukuzawa2008Interactions). The protein's ability to undergo reversible unfolding allows it to function as a molecular spring, absorbing mechanical stress and maintaining muscle cell integrity (Pinotsis2012Superhelical). Mutations in MYOM1 have been associated with muscle-related diseases, highlighting its significance in muscle function and pathology (Siegert2011A).

## Structure
Myomesin 1, encoded by the MYOM1 gene, is a structural protein found in the M-band of striated muscle sarcomeres. It consists of 1685 amino acids and features a modular structure with 13 domains, including a unique N-terminal domain, two immunoglobulin (Ig)-like domains, five fibronectin type III (Fn) domains, and five additional Ig-like domains (Hang2021Knockout; Lange2020The). The N-terminal domain binds to myosin, playing a crucial role in aligning thick filaments (Lamber2022The). The C-terminal region of myomesin 1 forms an antiparallel dimer, which is essential for the structural integrity and stabilization of the M-band (Hang2021Knockout; Lange2020The).

The protein's secondary structure includes α-helical linkers between Ig domains, contributing to its elasticity and function as a molecular spring (Lamber2022The). Myomesin 1 can undergo reversible unfolding, allowing it to stretch under mechanical stress, which is vital for its role as a shock absorber in muscle tissues (Lamber2022The; Pinotsis2012Superhelical).

Post-translational modifications, such as phosphorylation, may regulate myomesin 1's interactions and function, with a notable phosphorylation site at serine residue Ser482 affecting its binding affinity with titin (Obermann1997Molecular). Multiple splice variants of MYOM1 exist, leading to isoforms with potentially distinct roles in muscle tissue (Lange2020The).

## Function
MYOM1, or myomesin 1, is a protein that plays a critical role in the structural integrity and function of the sarcomere, particularly within the M-band of striated muscle cells. It acts as a structural linker by cross-linking myosin filaments and interacting with titin and obscurin, forming a ternary complex essential for M-band formation and myofibril stability (Fukuzawa2008Interactions). Myomesin 1 is involved in maintaining the transverse hexagonal lattice of myosin filaments, supporting the centering and alignment of the A-band during muscle contraction and relaxation (Lamber2022The).

The protein consists of 13 domains, including immunoglobulin-like and fibronectin type III domains, and forms antiparallel dimers that stabilize the contractile apparatus during muscle contraction (Siegert2011A). Myomesin 1's reversible elongation mechanism provides elasticity, allowing it to function as a molecular spring, which is crucial for maintaining muscle cell integrity under physiological tension (Lamber2022The).

MYOM1 is expressed in a nearly stoichiometrical ratio to sarcomeric myosin, indicating its essential role in muscle structure and function (Lange2020The). It is also involved in signaling muscle activity to the nucleus, affecting the transcription of sarcomeric genes (Lange2020The).

## Clinical Significance
Mutations in the MYOM1 gene, which encodes the protein myomesin-1, have been linked to several muscle-related diseases, particularly hypertrophic cardiomyopathy (HCM). A specific missense mutation, V1490I, in the MYOM1 gene has been identified in patients with HCM. This mutation affects the dimerization properties of myomesin, leading to reduced thermal stability and decreased dimerization affinity, which may contribute to the pathogenesis of HCM (Siegert2011A). The mutation follows an autosomal dominant inheritance pattern with age-related penetrance, typical for HCM, and has been associated with mild to moderate hypertrophy in affected individuals (Siegert2011A).

Alterations in MYOM1 expression are also linked to cardiac diseases. In dilated cardiomyopathy (DCM), an abnormal expression pattern of myomesin isoforms is observed, with elevated EH-myomesin expression and downregulation of myomesin-2, suggesting an adaptive mechanism for heart dilation (Lamber2022The). MYOM1 knockout studies in human cardiomyocytes have shown that its deficiency leads to myocardial atrophy, characterized by reduced myocardial volume and impaired calcium homeostasis, which are critical factors in cardiac function (Hang2021Knockout). These findings underscore the importance of MYOM1 in maintaining cardiac structure and function, with its disruption potentially leading to significant cardiovascular conditions.

## Interactions
Myomesin-1, encoded by the MYOM1 gene, is a crucial component of the M-band in muscle sarcomeres, where it interacts with several key proteins to maintain structural integrity and function. It forms an antiparallel dimer through its C-terminal Ig domains, linking symmetrical parts of the sarcomere and acting as a major absorber of mechanical stress (Lange2020The). Myomesin-1 interacts with titin and obscurin, forming a ternary complex at the M4/M4' lines, which is mechanically stable and involves dimerization interfaces on My4 and My5 domains (Lamber2022The). The interaction between myomesin-1 and obscurin involves the third Ig domain of obscurin interacting with a linker connecting FnIII domains of myomesin-1 (Lange2020The).

Myomesin-1 also binds to muscle-type creatine kinase (MM-CK) at the M-band, a unique interaction regulated by ionic strength (Lamber2022The). It interacts with titin and obscurin-like 1 (Obsl1), forming a complex that is essential for targeting obscurin and Obsl1 to the M-band, which is significant for understanding hereditary myopathies linked to the M-band (Fukuzawa2008Interactions). These interactions highlight the complex role of myomesin-1 in muscle integrity and its involvement in various protein complexes.


## References


[1. (Hang2021Knockout) Chengwen Hang, Yuanxiu Song, Ya’nan Li, Siyao Zhang, Yun Chang, Rui Bai, Amina Saleem, Mengqi Jiang, Wenjing Lu, Feng Lan, and Ming Cui. Knockout of myom1 in human cardiomyocytes leads to myocardial atrophy via impairing calcium homeostasis. Journal of Cellular and Molecular Medicine, 25(3):1661–1676, January 2021. URL: http://dx.doi.org/10.1111/jcmm.16268, doi:10.1111/jcmm.16268. This article has 15 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jcmm.16268)

[2. (Siegert2011A) Romy Siegert, Andreas Perrot, Sandro Keller, Joachim Behlke, Aleksandra Michalewska-Włudarczyk, Anna Wycisk, Michal Tendera, Ingo Morano, and Cemil Özcelik. A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties. Biochemical and Biophysical Research Communications, 405(3):473–479, February 2011. URL: http://dx.doi.org/10.1016/j.bbrc.2011.01.056, doi:10.1016/j.bbrc.2011.01.056. This article has 33 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2011.01.056)

[3. (Lange2020The) Stephan Lange, Nikos Pinotsis, Irina Agarkova, and Elisabeth Ehler. The m-band: the underestimated part of the sarcomere. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1867(3):118440, March 2020. URL: http://dx.doi.org/10.1016/j.bbamcr.2019.02.003, doi:10.1016/j.bbamcr.2019.02.003. This article has 70 citations.](https://doi.org/10.1016/j.bbamcr.2019.02.003)

[4. (Pinotsis2012Superhelical) Nikos Pinotsis, Spyros D. Chatziefthimiou, Felix Berkemeier, Fabienne Beuron, Irene M. Mavridis, Petr V. Konarev, Dmitri I. Svergun, Edward Morris, Matthias Rief, and Matthias Wilmanns. Superhelical architecture of the myosin filament-linking protein myomesin with unusual elastic properties. PLoS Biology, 10(2):e1001261, February 2012. URL: http://dx.doi.org/10.1371/journal.pbio.1001261, doi:10.1371/journal.pbio.1001261. This article has 37 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1371/journal.pbio.1001261)

[5. (Lamber2022The) Ekaterina P. Lamber, Pascale Guicheney, and Nikos Pinotsis. The role of the m-band myomesin proteins in muscle integrity and cardiac disease. Journal of Biomedical Science, March 2022. URL: http://dx.doi.org/10.1186/s12929-022-00801-6, doi:10.1186/s12929-022-00801-6. This article has 12 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/s12929-022-00801-6)

[6. (Fukuzawa2008Interactions) Atsushi Fukuzawa, Stephan Lange, Mark Holt, Anna Vihola, Virginie Carmignac, Ana Ferreiro, Bjarne Udd, and Mathias Gautel. Interactions with titin and myomesin target obscurin and obscurin-like 1 to the m-band – implications for hereditary myopathies. Journal of Cell Science, 121(11):1841–1851, June 2008. URL: http://dx.doi.org/10.1242/jcs.028019, doi:10.1242/jcs.028019. This article has 158 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.028019)

[7. (Obermann1997Molecular) W. M.J. Obermann. Molecular structure of the sarcomeric m band: mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin. The EMBO Journal, 16(2):211–220, January 1997. URL: http://dx.doi.org/10.1093/emboj/16.2.211, doi:10.1093/emboj/16.2.211. This article has 193 citations.](https://doi.org/10.1093/emboj/16.2.211)