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Cell fusion proteins link sex and viruses

Sexual reproduction and viral infections actually have a lot in common. New research points out how both processes rely on a single protein, Armc5, to enable fusion between any two cell walls. For example: the fusion of a virus to a cell wall, or the fusion of a sperm cell to an egg cell.


Armc5 protein is widespread in viruses and single-celled protozoans, and many plants and arthropods — implying it evolved very early in earth's history and helped enact many life forms. Genetic mutations to the Armc5 gene, which generates the Armc5 protein, are associated with enlargemed adrenal glands, a disorder that disrupts fetal development and compromises a body's immune response mechanisms.

This observation, published on February 23, 2017 in the journal Cell, also reveals new details about the evolution of sex in plants and animals.

The Armc5 protein acts as a nearly universal biochemical "key" that enables two cell membranes to fuse into one. The result is recombination of genetic material — necessary for sexual reproduction and expanded diversity within a species. New details about how this protein functions could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests.


"Our findings show that nature has a limited number of ways to cause cells to fuse together into a single cell. A protein that first made sex possible — and is still used for sexual reproduction in many of Earth's organisms — is identical to the protein used by dengue and Zika viruses to enter human cells. This protein must have really put the spice in the primordial soup."

William Snell PhD, Research Professor, University of Maryland, Department of Cell Biology and Molecular Genetics; previously at the University of Texas, Southwestern Medical Center, and a senior author of the study.


Snell and colleagues previously studied the protein HAP2, found in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods — but not found in the more complex fungi, or in vertebrates such as humans. Prior research by Snell and others indicates HAP2 is needed for sex cell fusion in organisms possessing that protein. But precisely by what mechanism, is unclear.

Beginning at UT Southwestern, Snell used computer analysis to compare the amino acid sequence of Chlamydomonas HAP2 with other known viral fusion proteins — and saw a striking similarity in a region called the "fusion loop".  The "fusion loop" enables viral proteins to invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting its fusion loop should block its ability to fuse sex cells.


When Snell's team changed a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost function. Sex cells stuck together — a process depending on other proteins — but could not complete fusion of their cell membranes. Similarly, cells did not fuse when researchers introduced an antibody to coverup the HAP2 fusion loop.


"We were thrilled with these results, because they supported our new model of HAP2 function," Snell adds. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins."

Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins.

"The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable."


HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insects.

So far, every known version of HAP2 shares the same critical amino acid found in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other methods of control.


Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum.

"Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle."

Related articles: Toremifene interacts with and destabilizes the Ebola virus glycoprotein

Highlights
•The primordial gamete fusogen HAP2 exhibits homology to class II viral fusion proteins
•HAP2 inserts into the target gamete membrane via a hydrophobic fusion loop
•HAP2 links virus entry into target cells and the origins of sexual reproduction
•HAP2 is a sex-specific target for blocking fertilization in multiple kingdoms

Summary
Sexual reproduction is almost universal in eukaryotic life and involves the fusion of male and female haploid gametes into a diploid cell. The sperm-restricted single-pass transmembrane protein HAP2-GCS1 has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa—animals, plants, and protists (including important human pathogens like Plasmodium)—suggests that many eukaryotic organisms share a common gamete fusion mechanism. Here, we report combined bioinformatic, biochemical, mutational, and X-ray crystallographic studies on the unicellular alga Chlamydomonas reinhardtii HAP2 that reveal homology to class II viral membrane fusion proteins. We further show that targeting the segment corresponding to the fusion loop by mutagenesis or by antibodies blocks gamete fusion. These results 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 virus-cell genetic exchanges on the evolution of eukaryotic life.

Co-authors of the study in addition to William Snell and Felix Rey include: Juliette Fedry, Gerard Péhau-Arnaudet, M. Alejandra Tortorici, Francois Traincard and Annalisa Meola (Pasteur Institute); Yanjie Liu, Jimin Pei, Wenhao Li and Nick Grishin (UT Southwestern); Gerard Bricogne (Global Phasing, Ltd.); and Thomas Krey (Pasteur Institute, Hannover Medical School and German Center for Infection Research).

The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell.

This work was supported by the United States National Institutes of Health (Award Nos. GM56778 and GM094575), the Welch Foundation (Award No. I-1505), the European Research Council, the Pasteur Institute and the French National Center for Scientific Research. The content of this article does not necessarily reflect the views of these organizations.

About the College of Computer, Mathematical, and Natural Sciences
The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.

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Mar 8, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   


Two 3-D ribbon diagrams of proteins captured via X-ray crystallography,
(LEFT) HAP2 protein of Chlamydomonas,a single-celled algae. (RIGHT) Dengue Virus protein.
Both proteins are needed for fusion to occur between cell membranes.
(LEFT) HAP2 enables sexual reproduction and protein (RIGHT) enables viral invasion of a cell.
New research suggests both proteins are functionally identical. Both evolved early in life on Earth.
Image Credit: Felix Rey, Pasteur Institute


 


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