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Celcelfus Report Summary

Project ID: 340371
Funded under: FP7-IDEAS-ERC
Country: France

Mid-Term Report Summary - CELCELFUS (Cell-Cell fusion in fertilization and developmental biology: a structural biology approach)

One major achievement of the Celcelfus project has been the determination of the crystal structure of protein HAP2, which is involved in the process of membrane fusion during sexual reproduction. This is an almost universal feature in eukaryotic life, and involves the fusion of male and female haploid gametes toform a diploid cell. HAP2 is a sperm- restricted single-transmembrane protein, which has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa – animals, plants, protists (including pathogens like Plasmodium, Trypanosoma and Leishmania) - suggests that most eukaryotic organisms share a common gamete fusion mechanism. We used a combined bioinformatic, biochemical, mutational and X-ray crystallographic studies on HAP2 from the unicellular alga Chlamydomonas reinhardtii, revealing homology to class II viral fusion proteins. We further show that targeting the segment identified as potential fusion loop by mutagenesis or by antibodies blocks gamete fusion. Our results thus 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 genetic exchanges between viruses and cells on the evolution of eukaryotic life. This work has been submitted for publication and it is in the process of being peer-reviewed.
Other aspects of the work have been the characterization of the pre-fusion form of the cell-cell fusion protein EFF-1, and implementing the conditions to obtain also its structure in the presence of the trans-membrane anchors, which we postulated form a coiled coil zippering the two membranes together during cell-cell fusion.

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