Fusexins, HAP2/GCS1 and Evolution of Gamete Fusion

Abstract

Gamete fusion is the climax of fertilization in all sexually reproductive organisms, from unicellular fungi to humans. Similarly to other cell-cell fusion events, gamete fusion is mediated by specialized proteins, named fusogens, that overcome the energetic barriers during this process. 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. The identification of HAP2/GCS1 in invertebrates, opens the possibility that a similar fusogen may be used in vertebrate fertilization. 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). Altogether, these fusogens form the Fusexin superfamily. 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. 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. Here, we discuss the biology of HAP2/GCS1, its involvement in gamete fusion and the structural, mechanistic and evolutionary relationships with other fusexins.

IZUMO1 is a sperm fusogen

“…Up to this report, GCS1/HAP2 proteins were the only known fusogens involved in fertilization (reviewed in (Brukman et al, 2022)); these proteins are structurally and evolutionarily related to Class II fusogens from enveloped viruses and FF fusogens from nematodes (Fédry et al, 2017; Pinello et al, 2017; Valansi et al, 2017). Together, these fusogens form a superfamily called Fusexins.…”

“…Remarkably, structural analysis of GCS1/HAP2 from different species showed a shared tertiary and quaternary organization with class II viral glycoproteins (such as those from dengue, rubella and zika viruses) (Fédry et al, 2017; Pinello et al, 2017; Valansi et al, 2017) and with Fusion Family (FF) proteins from nematodes and other organisms (Avinoam et al, 2011; Mohler et al, 2002; Pérez-Vargas et al, 2014; Sapir et al, 2007). This protein superfamily, termed Fusexins (Valansi et al, 2017), are widely distributed in multiple phyla, but to date no members have been identified in vertebrates (Brukman et al, 2022; Vance and Lee, 2020).…”

Ciliate research: From myth to trendsetting science

“…Thus, there would have been ample time for viruses to interfere with evolution of ciliates, perhaps with reproduction pathways. This view is supported by the similarity of fusogenic proteins of the superfamily of Fusexins, such as HAP2, from some viruses (Rubella, Dengue virus), ciliates (conjugation of ciliates; Cole et al, 2014) and other protists, up to gamete fusion in mammals (Brukman et al, 2022).…”

Discovery of archaeal fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins

“…More recently it was shown that myoblast fusion requires two unrelated proteins to form muscles in vertebrates 7 , 8 . However, many fusogens have not been identified yet, and the molecular basis of gamete fusion in fungi and vertebrates remain unclear 9 .…”