Cellular fusion: Protein X-ray insights

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  • Published: Mar 1, 2017
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Cellular fusion: Protein X-ray insights

Sex cells

X-ray crystallography reveals that two closely related proteins, the HAP2 protein from the single-celled alga Chlamydomonas reinhardtii and the fusion protein from dengue virus are essential for fusion with a cell membrane and thus both sexual reproduction and viral invasion of a host cell. The proteins probably emerged very early in the history of life on Earth. (Image credit: Felix Rey, Pasteur Institute)

The link between sex and viruses isn't necessarily what you imagine. The molecular biology of sexual reproduction and viral infection have a lot in common at the protein level. X-ray crystallography reveals that two closely related proteins, the HAP2 protein from the single-celled alga Chlamydomonas reinhardtii and the fusion protein from dengue virus are essential for fusion with a cell membrane and thus both sexual reproduction and viral invasion of a host cell. The proteins probably emerged very early in the history of life on Earth.

The seamless fusion of sperm and egg cells share protein biochemistry with the fusion of a virus with a cell membrane. The protein is widespread among viruses, single-celled protozoans, and many plants and arthropods, according to research by an international team. William Snell of the University of Maryland (formerly University of Texas Southwestern Medical Center), Juliette Fedry, Gerard Péhau-Arnaudet, Alejandra Tortorici, Francois Traincard and Annalisa Meola of the Pasteur Institute, Yanjie Liu, Jimin Pei, Wenhao Li, and Nick Grishin of UT Southwestern, Gerard Bricogne of Global Phasing, Ltd, and Thomas Krey of the Pasteur Institute, Hannover Medical School and German Center for Infection Research undertook the research.

The ribbon diagrams shown reveal details of the X-ray structures of the HAP2 protein from the single-celled alga Chlamydomonas reinhardtii (pictured left) and on the right the fusion protein from dengue virus. Writing in the journal Cell at the end of February, the team explains how the protein acts as something of a universal, biochemical key allowing the membranes of two cells to fuse and so facilitating the combining of genetic material, either sexual reproduction or in viral infection. The team hints that the new insights could help target parasitic diseases, such as malaria, and even boost efforts to control insect pests.

Fusion theory

"Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," explains Snell. "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," he adds.

The researchers investigated the common protein, HAP2, which is not present in fungi nor vertebrates). Their earlier work and results from other groups had already suggested that HAP2 is necessary for sex cell fusion in organisms that have this protein, the new work offers a plausible mechanism for this process.

Snell and his colleagues at UT Southwestern used computer analysis to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins and found that there was a striking degree of similarity, especially in a region called the "fusion loop". If HAP2 functions in the manner of a viral fusion protein, then perhaps inhibiting this active region would block the ability to fuse sex cells. When they created a mutated version of the protein with just a single amino acid changed in the fusion loop functionality was lost: final fusion of gamete cell membranes did not occur. Similarly, an antibody that masked the fusion loop had the same devastating impact on cell fusion.

The thrill of it all

"We were thrilled with these results, because they supported our new model of HAP2 function," Snell says. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." By sheer coincidence, Colleague Félix Rey, a structural biologist and viral specialist at the Pasteur Institute in Paris Coincidentally, and his colleagues had recently determined the X-ray structure of Chlamydomonas HAP2. The team combined their data to demonstrate that 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 explains. "The resemblance is unmistakable."

HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including pathogenic protozoa, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies, and other control methods in medicine and agriculture. 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," he enthuses. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." Snell told SpectroscopyNOW that, "From a human perspective, I am most excited about our discovery that a tiny piece of Chlamydomonas HAP2 (only 20 amino acids long) can be used to generate antibodies that block fusion of Chlamydomoas gametes. If this works for Chlamydomonas HAP2, it might very well work for Plasmodium HAP2 and thereby open the way to a transmission blocking malaria vaccine."

Related Links

Cell, 2017, online: "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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