elegans’ EFF-1 ( CeEFF-1), and HAP2/GCS1 are structurally homologous to viral class II fusion proteins and display a trimeric, postfusion hairpin conformation consisting of three β-sheet-rich domains (DI, DII, DIII) ( Figure 1) ( Pérez-Vargas et al., 2014 Fédry et al., 2017 Pinello et al., 2017 Valansi et al., 2017). Previous studies have shown FF proteins, like C. Structural Similarities and Differences Between Fusexins Furthermore, we compare the regulation of fusion processes driven by fusexins to the fertilization process in mammals, where the presence of distant members of the Fusexin superfamily is uncertain. Here we review the recent research on HAP2/GCS1-mediated gamete fusion and its functional and structural relationships with other fusexins. Even though the mechanisms of cell-cell and virus-cell fusion are diverse and may be mediated by different families of fusion proteins ( Segev et al., 2018 Vance and Lee, 2020), the fusexins represent a remarkable case of ancestral fusogens present across the tree of life. This superfamily of fusion proteins essential for sexual reproduction and exoplasmic merger of plasma membranes was named Fusexin. Strikingly, HAP2/GCS1 shares an overall three-dimensional structure with the somatic Fusion Family (FF) proteins discovered in nematodes ( Mohler et al., 2002 Sapir et al., 2007 Pérez-Vargas et al., 2014) and with class II viral glycoproteins (e.g., dengue, rubella and zika viruses) ( Fédry et al., 2017 Pinello et al., 2017 Valansi et al., 2017). More recently, the Arabidopsis HAP2/GCS1 ( AtHAP2/GCS1) was shown to be sufficient to induce fusion of mammalian cells in culture and the infection of enveloped virus to cells ( Valansi et al., 2017). This protein was originally found as an essential sperm factor required for male fertility in flowering plants ( Johnson et al., 2004 Mori et al., 2006 von Besser et al., 2006) being later shown that it is necessary for mating in Chlamydomonas and Plasmodium ( Hirai et al., 2008 Liu et al., 2008). The first gamete fusogen identified was HAPLESS 2/GENERATIVE CELL-SPECIFIC 1 (HAP2/GCS1) that catalyzes fertilization in flowering plants, protists and probably in some invertebrates. In particular, the fusion between two gametes or “gamete fusion” is one of the hallmarks of meiotic sex and its ubiquitous distribution among eukaryotes suggests an ancestral origin ( Ramesh et al., 2005 Speijer et al., 2015 Radzvilavicius, 2016). This biological process is mediated and finely controlled by fusion proteins, termed fusogens, which are specialized proteins capable of overcoming the energetic barriers required for the fusion to occur ( Chernomordik and Kozlov, 2003) and are both necessary and sufficient to mediate membrane merging ( Brukman et al., 2019). The merging of the plasma membranes of two independent cells with the subsequent formation of an individual cell containing both cytoplasmic contents mixed is known as cell-cell fusion. ![]() Here, we discuss the biology of HAP2/GCS1, its involvement in gamete fusion and the structural, mechanistic and evolutionary relationships with other fusexins. Intriguingly, HAP2/GCS1 or other fusexins have neither been identified in vertebrates nor in fungi, raising the question of whether these genes were lost during evolution and were replaced by other fusion machinery or a significant divergence makes their identification difficult. While some attributes are shared among fusexins, for example the overall structure and the possibility of assembly into trimers, some other characteristics seem to be specific, such as the presence or not of hydrophobic loops or helices at the distal tip of the protein. Altogether, these fusogens form the Fusexin superfamily. HAP2/GCS1 proteins share a similar structure with two distinct families of exoplasmic fusogens: the somatic Fusion Family (FF) proteins discovered in nematodes, and class II viral glycoproteins (e.g., rubella and dengue viruses). The identification of HAP2/GCS1 in invertebrates, opens the possibility that a similar fusogen may be used in vertebrate fertilization. ![]() In recent years, HAPLESS 2/GENERATIVE CELL-SPECIFIC 1 (HAP2/GCS1) was identified as the fusogen mediating sperm-egg fusion in flowering plants and protists, being both essential and sufficient for the membrane merger in some species. ![]() ![]() Similarly to other cell-cell fusion events, gamete fusion is mediated by specialized proteins, named fusogens, that overcome the energetic barriers during this process. Gamete fusion is the climax of fertilization in all sexually reproductive organisms, from unicellular fungi to humans.
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