The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein

Summary Sexual reproduction is almost universal in eukaryotic life and involves the fusion of male and female haploid gametes into a diploid cell. The sperm-restricted single-pass transmembrane protein HAP2-GCS1 has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa—animals, plants, and protists (including important human pathogens like Plasmodium)—suggests that many eukaryotic organisms share a common gamete fusion mechanism. Here, we report combined bioinformatic, biochemical, mutational, and X-ray crystallographic studies on the unicellular alga Chlamydomonas reinhardtii HAP2 that reveal homology to class II viral membrane fusion proteins. We further show that targeting the segment corresponding to the fusion loop by mutagenesis or by antibodies blocks gamete fusion. These results demonstrate that HAP2 is the gamete fusogen and suggest a mechanism of action akin to viral fusion, indicating a way to block Plasmodium transmission and highlighting the impact of virus-cell genetic exchanges on the evolution of eukaryotic life.
Graphical Abstract
Highlights • The primordial gamete fusogen HAP2 exhibits homology to class II viral fusion proteins • HAP2 inserts into the target gamete membrane via a hydrophobic fusion loop • HAP2 links virus entry into target cells and the origins of sexual reproduction • HAP2 is a sex-specific target for blocking fertilization in multiple kingdoms
Gamete fusion across eukaryotic branches uses an ancient factor homologous to viral fusion proteins.