1.N.2 The Myoblast Fusion Complex (MFC) Family Existing evidence suggests that several proteins may be involved in myoblast fusion is various systems (Schejter 2016). The principal protein constituents that could mediate myoblast pore-formatioin and fusion are (1) annexins A1 and A5, Ca²⁺-regulated phospholipid binding proteins (TC# 1.A.31.1.3 and, 1.7, respectively), Singles-bar (Sing) with a MARVEL domain (TC# 9.A.69.1.1), present in Drosophila, and human Myomaker, a transmembrane (7 TMS) myoblast fusogen, also known as Tmem8c, that increases fusion rates in humans, fruit flies, chickens and zebrafish (Schejter 2016). Myomaker may mediate fusioin of several types of cells in additioin to myoblasts. In C. elegans, there are proteins called FF fusogens (TC#9.A.68.1.1) that may mediate cell fusion. Other proteins that can mediate fusion in humans are the Syncytins (TC# 1.G.9.1.1). Reviewed by Hernández and Podbilewicz 2017. Classic mechanisms for membrane fusion involve transmembrane proteins that assemble into complexes and dynamically alter their conformation to bend membranes, leading to mixing of membrane lipids (hemifusion) and fusion pore formation. Myomaker and Myomerger (Mymk; Minion) govern myoblast fusion and muscle formation but are structurally divergent from traditional fusogenic proteins. Leikina et al. 2018 showed that Myomaker and Myomerger independently mediate distinct steps in the fusion pathway, where Myomaker is involved in membrane hemifusion and Myomerger is necessary for fusion pore formation. Myomerger is required on the cell surface where its ectodomains stress membranes, but Myomerger drives fusion completion in a heterologous system independently of Myomaker. Moreover, a Myomaker-Myomerger physical interaction is not required for function. Thus, a stepwise cell fusion mechanism in myoblasts where different proteins are delegated to perform unique membrane functions essential for membrane coalescence is suggested (Leikina et al. 2018).
References:
Bi, P., A. Ramirez-Martinez, H. Li, J. Cannavino, J.R. McAnally, J.M. Shelton, E. Sánchez-Ortiz, R. Bassel-Duby, and E.N. Olson. (2017). Control of muscle formation by the fusogenic micropeptide myomixer. Science 356: 323-327.
Goh, Q. and D.P. Millay. (2017). Requirement of myomaker-mediated stem cell fusion for skeletal muscle hypertrophy. Elife 6:.
Hernández, J.M. and B. Podbilewicz. (2017). The hallmarks of cell-cell fusion. Development 144: 4481-4495.
Jia, X., H. Lin, B.A. Abdalla, and Q. Nie. (2016). Characterization of miR-206 Promoter and Its Association with Birthweight in Chicken. Int J Mol Sci 17: 559.
Landemaine, A., P.Y. Rescan, and J.C. Gabillard. (2014). Myomaker mediates fusion of fast myocytes in zebrafish embryos. Biochem. Biophys. Res. Commun. 451: 480-484.
Leikina, E., D.G. Gamage, V. Prasad, J. Goykhberg, M. Crowe, J. Diao, M.M. Kozlov, L.V. Chernomordik, and D.P. Millay. (2018). Myomaker and Myomerger Work Independently to Control Distinct Steps of Membrane Remodeling during Myoblast Fusion. Dev Cell. [Epub: Ahead of Print]
Peng, S.P., X.L. Li, L. Wang, J. Ou-Yang, J. Ma, L.L. Wang, H.Y. Liu, M. Zhou, Y.L. Tang, W.S. Li, X.M. Luo, L. Cao, K. Tang, S.R. Shen, and G.Y. Li. (2006). The role of NGX6 and its deletion mutants in the proliferation, adhesion and migration of nasopharyngeal carcinoma 5-8F cells. Oncology 71: 273-281.
Schejter, E.D. (2016). Myoblast fusion: Experimental systems and cellular mechanisms. Semin Cell Dev Biol. [Epub: Ahead of Print]
Zhang, W. and S. Roy. (2017). Myomaker is required for the fusion of fast-twitch myocytes in the zebrafish embryo. Dev Biol 423: 24-33.
Examples:
TC#	Name	Organismal Type	Example
1.N.2.1.1	Myomaker (Tmem8c) of 221 aas and 7 TMSs and Myomerger/Mymx/Minion of 84 aas and at least 1 N-terminal TMS, although there may be as many as 3 TMSs. These two proteins were thought to be myoblast-specific proteins that mediate myoblast fusion, essential for the formation of multi-nucleated muscle fibers. They actively participate in the membrane fusion reaction (Schejter 2016). Fusion is dependent on the fusogenic peptide, myomixer (Bi et al. 2017). Myomaker is also required for stem cell fusion in skeletal muscle (Goh and Millay 2017). While Myomaker initiates the fusion process by creating the hemifusion intermediate, Myomerger (Myomixer) is the fusogenic peptide that completes the fusion of the two membranes by formation of a continuous bilayer (Leikina et al. 2018). Reviewed by Hernández and Podbilewicz 2017.		Myomaker/Myomerger of Homo sapiens

1.N.2.1.2	Myomaker homologue of 993 aas		*Myomaker homologue of Drosophila melanogaster* (Fruit fly)**

1.N.2.1.3	*Myomaker; Tmem8c of 220 aas and 7 TMSs (Jia et al.* 2016).**		*Tmem8c of Gallus gallus* (Chicken)**

1.N.2.1.4	Myomaker (Tmem8c) of 220 aas and 7 TMSs. Essential for myocyte fusion in zebrafish (Landemaine et al. 2014). Myomaker is necessary for fast twitch myocyte fusion in zebrafish embryos (Zhang and Roy 2017).		Myomaker of Danio rerio (Zebrafish) (Brachydanio rerio)

1.N.2.1.5	Tmem8b of 605 aas and 8 TMSs.		*Tmem8b of Daphnia pulex* (Water flea)**

1.N.2.1.6	Tmem8a of 771 aas and 7 or more TMSs		Tmem8a of Homo sapiens

1.N.2.1.7	*Tmem8b of 472 aas and 7 TMSs. May function as a regulator of the EGFR pathway. Probable tumor suppressor which may function in cell growth, proliferation and adhesion (Peng et al.* 2006).**		Tmem8b of Homo sapiens