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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.

Author information

1
Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
2
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
3
Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. Electronic address: tgc3@cornell.edu.

Abstract

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.

KEYWORDS:

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

PMID:
28238660
PMCID:
PMC5393271
DOI:
10.1016/j.cub.2017.01.049
[Indexed for MEDLINE]
Free PMC Article

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