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Curr Biol. 2017 Mar 6;27(5):651-660. doi: 10.1016/j.cub.2017.01.049. Epub 2017 Feb 23.

Structure-Function Studies Link Class II Viral Fusogens with the Ancestral Gamete Fusion Protein HAP2.

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Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. Electronic address:


The conserved transmembrane protein, HAP2/GCS1, has been linked to fertility in a wide range of taxa and is hypothesized to be an ancient gamete fusogen. Using template-based structural homology modeling, we now show that the ectodomain of HAP2 orthologs from Tetrahymena thermophila and other species adopt a protein fold remarkably similar to the dengue virus E glycoprotein and related class II viral fusogens. To test the functional significance of this predicted structure, we developed a flow-cytometry-based assay that measures cytosolic exchange across the conjugation junction to rapidly probe the effects of HAP2 mutations in the Tetrahymena system. Using this assay, alterations to a region in and around a predicted "fusion loop" in T. thermophila HAP2 were found to abrogate membrane pore formation in mating cells. Consistent with this, a synthetic peptide corresponding to the HAP2 fusion loop was found to interact directly with model membranes in a variety of biophysical assays. These results raise interesting questions regarding the evolutionary relationships of class II membrane fusogens and harken back to a long-held argument that eukaryotic sex arose as the byproduct of selection for the horizontal transfer of a "selfish" genetic element from cell to cell via membrane fusion.


GCS1; HAP2; Tetrahymena; conjugation; evolution of sex; membrane fusion; structure homology modeling; virus fusogen

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