Discovering the origins of egg-sperm fusion

11-07-2022

An international team of researchers has obtained key insights into the origin of egg-sperm fusion. They used X-ray crystallography on the ESRF’s beamlines. Their results are published in Nature Communications.

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The fusion of egg and sperm, specialized cells that carry the genetic information for the next generation, is the climax of sexual reproduction. How do two sexual cells fuse to become one? Uncontrolled cell fusion is lethal, so plants and animals use special proteins called fusogens to control when and where this process takes place. Notably, even simple single-cell organisms can exchange genetic material, but how they connect with each other for doing so remains unclear.

With the aim of finding answers, an international, interdisciplinary team of scientists, led by Karolinska Institutet, Technion-Israel Institute of Technology, CONICET in Argentina, Universidad de la República and Institut Pasteur in Uruguay, and University of Lausanne in Switzerland joined forces. They have now shown that bacteria-like cells believed to have originated more than 3 billion years ago, called Archaea, can contain a protein (Fusexin 1 or Fsx1) that resembles a type of fusogens (HAP2) previously identified in viruses, plants and invertebrate animals.

Gamete fusion has fascinated mankind for more than 150 years. The finding that HAP2-like proteins are also used to fuse the membrane of enveloped viruses (such as zika, dengue and rubella) with host cells opened the question of whether this key molecule originated in a virus and was then repurposed for gamete fusion in plants and animals, or the other way around. The discovery that ancient creatures like Archaea can also contain an HAP2-like protein now raises a third intriguing possibility, whereby Fusexin1 is the ancestral molecule from which viral, plant and animal fusogens derived.

The researchers teamed up with scientists at the ESRF and the AI company DeepMind. “We combined computational evolutionary biology, AlphaFold-based protein modeling, X-ray crystallography at the ESRF and functional studies to show that archaeal protein Fsx1 is a fusogen”, explains Luca Jovine, who led the structural biology part of the study. This is because Fsx1, despite lack of significant sequence identity, is structurally similar to the previously identified HAP2 fusogens, and because the protein is able to promote cell-cell fusion when expressed in other cell types. “With Luca Jovine we have a long-standing collaboration in structural biology since a long time ago. Today, with the combination of X-ray crystallography and artificial intelligence, we are living the next revolution, opening the doors to new discoveries and a brighter future for structural biology”, explains Daniele de Sanctis, scientist at the ESRF and co-author of the study.

The next step will be to find out what Fsx1 proteins are doing in nature: do they fuse archaeal cells, like their plant and animal HAP2 counterparts fuse gametes, to promote a sex-like DNA exchange? In parallel, the team will try to chart the evolutionary history connecting Fsx1 and HAP2, in order to establish firmly what their origin is. “We hope that all this knowledge will help to understand how cells evolved from apparently simple forms sharing discrete pieces of DNA to today’s complex life forms undergoing sexual reproduction”, concludes Jovine.

Reference:

Moi, D., et al. Nat Commun 13, 3880 (2022). https://doi.org/10.1038/s41467-022-31564-1

Top image: Crystal structure of Fusexin1, determined using data collected at ESRF beamline ID23-1. Archaeal species with fusexins thrive in hypersaline environments like salt lakes, oceans and salterns. Credits: Luca Jovine.