PT - JOURNAL ARTICLE AU - David Moi AU - Shunsuke Nishio AU - Xiaohui Li AU - Clari Valansi AU - Mauricio Langleib AU - Nicolas G. Brukman AU - Kateryna Flyak AU - Christophe Dessimoz AU - Daniele de Sanctis AU - Kathryn Tunyasuvunakool AU - John Jumper AU - Martin Graña AU - Héctor Romero AU - Pablo S. Aguilar AU - Luca Jovine AU - Benjamin Podbilewicz TI - Discovery of archaeal Fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins AID - 10.1101/2021.10.13.464100 DP - 2022 Jan 01 TA - bioRxiv PG - 2021.10.13.464100 4099 - http://biorxiv.org/content/early/2022/04/16/2021.10.13.464100.short 4100 - http://biorxiv.org/content/early/2022/04/16/2021.10.13.464100.full AB - Sexual reproduction consists of genome reduction by meiosis and subsequent gamete fusion. Presence of meiotic genes in prokaryotes suggests that DNA repair mechanisms evolved toward meiotic recombination; however, fusogenic proteins resembling those found in eukaryotes were not identified in prokaryotes. Here, we identify archaeal proteins that are homologs of fusexins, a superfamily of fusogens that mediate eukaryotic gamete and somatic cell fusion, as well as virus entry. The crystal structure of a trimeric archaeal Fusexin1 reveals novel features such as a six-helix bundle and an additional globular domain. Ectopically expressed Fusexin1 can fuse mammalian cells, and this process involves the additional domain and a conserved fusion loop. Archaeal fusexin genes exist within integrated mobile elements, potentially linking ancient archaeal gene exchanges and eukaryotic sex.One-Sentence Summary Cell membrane fusion proteins of viruses and eukaryotes are also present in archaea.Competing Interest StatementJ.J. has filed provisional patent applications relating to machine learning for predicting protein structures. The other authors declare no competing interests.