RT Journal Article SR Electronic T1 Discovery of archaeal Fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.10.13.464100 DO 10.1101/2021.10.13.464100 A1 David Moi A1 Shunsuke Nishio A1 Xiaohui Li A1 Clari Valansi A1 Mauricio Langleib A1 Nicolas G. Brukman A1 Kateryna Flyak A1 Christophe Dessimoz A1 Daniele de Sanctis A1 Kathryn Tunyasuvunakool A1 John Jumper A1 Martin Graña A1 Héctor Romero A1 Pablo S. Aguilar A1 Luca Jovine A1 Benjamin Podbilewicz YR 2022 UL http://biorxiv.org/content/early/2022/04/16/2021.10.13.464100.abstract 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.