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Following ten years' research, the laboratories of Professor Félix Rey of the Institut Pasteur (Paris) and Professor Benjamin Podbilewicz, of Technion (Israel) have recently described the first three-dimensional structure (in other words, the spatial arrangement of atoms within a molecule) of a protein responsible for cell-cell fusion. This work, published in the latest edition of the journal Cell, provides essential information for understanding the mechanism of action of these fusogenic proteins.
Cell fusion occurs in a wide variety of physiological processes: fertilization (fusion of gametes, or sperm/egg fusion), muscle and bone morphogenesis, and also tissue regeneration following injury. It also plays a part in pathological processes such as cancer, when the fusion of tumor cells and healthy cells leads to metastasis formation. Despite the fundamental nature of these processes, until now there has been very little information available at the molecular level relating to the mechanisms that enable these proteins to carry out their fusogenic role. This study was carried out on a model organism, the nematode Caenorhabditis elegans (a roundworm), in which the EFF-1 protein mediates the fusion of skin cells during embryonic development. EFF-1 is the first cell fusion protein to be characterized in such detail. Its structure was determined using X-ray crystallography, by using the synchrotron beam SOLEIL (in St Aubin, near Paris), the Swiss Light Source (near Zurich) and the European synchrotron radiation facility (in Grenoble).
A surprising homology with the chikungunya virus
The most surprising result of this study is that the EFF-1 structure is very similar to that of certain viral envelope proteins, such as those of the chikungunya or dengue viruses, which had already been described by Félix Rey's laboratory at the Institut Pasteur. These viruses are surrounded by a lipid membrane, in which viral envelope proteins are anchored. These viral envelope proteins are responsible for fusion of the viral and target cell membranes, thereby enabling the virus to invade the cell.
Comparison of EFF-1 structure with these viral envelope proteins clearly shows that they are homologs, in other words they are derived from the same ancestral gene, taken over by both viruses and cells for exactly the same purpose: to induce membrane fusion. This result illustrates the importance of genetic material exchanges taking place between viruses and cells. These exchanges have been a driver of evolutionary change and appear to have contributed to the emergence of multicellular organisms.
These results pave the way for the identification of new proteins responsible for fusion processes in humans, which are also likely to have links with viral proteins. The only known example to date is syncytin, a protein that, by mediating cell fusion, is involved in placental formation in humans and other mammals. Studies had already shown that syncytin is the envelope protein of a retrovirus, the genes of which were integrated into the chromosomes of cells in the germ line – in other words, the cells that generate gametes, which transmit genetic information to future generations. It appears that integration of the genetic material of this virus into the genome of the cell enabled the evolution of a functional placenta, and that this encouraged mammalian development.
Structural basis of eukaryotic cell-cell fusion, Cell, Volume 157, Issue 2, April 10, 2014
Jimena Pérez-Vargas 1,2,8,9, Thomas Krey 1,2,8, Clari Valansi 3, Ori Avinoam 3,10, Ahmed Haouz4, Marc Jamin 5,6,7, Hadas Raveh-Barak 3, Benjamin Podbilewicz 3 and Félix A. Rey 1,2
1 Institut Pasteur, Structural Virology Unit, Paris, France
2 CNRS UMR 3569, Paris, France
3 Technion- Israel Institute of Technology, Department of Biology, Haifa, Israel
4 Institut Pasteur, Proteopole - Crystallogenesis Platform, CNRS UMR 3528, Paris, France
5 Grenoble Alps University, UVHCI, Grenoble, France
6 CNRS, UVHCI, Grenoble, France
7 Unit for Virus Host-Cell Interactions, Grenoble Alps University-EMBL-CNRS, Grenoble, France