The researchers used Google DeepMind’s AlphaFold artificial intelligence tool, whose developers were awarded the Nobel Prize in Chemistry earlier this month, to reveal how sperm proteins interact at a molecular level, shedding light on a fundamental aspect of fertilization shared among vertebrates.
Fertilization begins when sperm travel to the egg, guided by chemical signals. Once it reaches the egg, the sperm attaches to the surface of the egg, causing its genetic material to fuse to form the zygote (the fertilized egg). However, the precise molecular mechanisms that allow this crucial interaction have remained elusive.
Andrea Pauli’s lab at the Research Institute for Molecular Pathology (IMP) in Vienna, along with international collaborators, used AlphaFold Multimer to predict the protein interactions that direct sperm-egg fusion.
The team focused on sperm membrane proteins, using AlphaFold to predict which proteins might bind together. Their analysis revealed that two previously known proteins, Izumo1 and Spaca6, interact with a third, newly discovered protein, Tmem81.
Andreas Blaha, co-author of the study, said: “We were surprised to discover a new protein that had not been described before. This new ternary complex, composed of Izumo1, Spaca6 and Tmem81, has been shown to play a crucial role in fertilization. “When this compound was inactivated, male zebrafish and mice became sterile.”
The researchers showed that this sperm protein complex interacts with a zebrafish egg surface protein, known as Bouncer, which acts as a “lock,” allowing the sperm to fuse with the egg. The role of Bouncer in zebrafish is similar to that of Juno in mammals, although these proteins are evolutionarily unrelated.
This discovery suggests that while sperm proteins have remained conserved across species, egg proteins have evolved independently to facilitate fertilization in different vertebrates.
“The fact that they have been preserved over millions of years of evolution shows how important this lock-and-key process is,” noted Andrea Pauli, lead author of the study.
The researchers validated their AI-generated predictions through experiments on living organisms, confirming that this protein compound is present not only in zebrafish, but also in mice and humans. This suggests that the same sperm protein complex could be a universal feature of vertebrate fertilization.
This discovery opens new horizons for exploring fertility and reproductive health treatments, as the proteins involved are essential for the fusion process.
The researchers are eager to explore how various egg proteins have evolved in different species to interact with the conserved sperm machinery.
The study was published in the journal Cell.
Source: Interesting Engineering
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