They are the original odd pair: one is huge, spherical and immovable. The other is smaller, has a tail and won’t stop swimming. However, the fusion of egg and sperm is important to every sexually reproducing animal on Earth.
How that union occurs has long been a mystery to scientists. A study A study published Thursday in the journal Cell that relies on Nobel Prize-winning artificial intelligence technology shows that an interconnected bundle of three proteins helps bind sperm and egg together. That important bundle is shared by distantly related animals such as fish and mammals, and often including humans.
For all animals on Earth, life begins with a sperm cell making its way to the cell membrane of an egg. Somehow, the two cells recognize each other and fuse together. Then, in a flash, the sperm head enters the egg as if entering through a door. Now the fused cell is a zygote and ready to grow into a new animal.
In previous research, scientists have identified four proteins in mammalian sperm that are also present in fish sperm and are required for fertilization. But no one knows if, or how, they will work as a team to hatch an egg.
In the new study, Andrea Pauli, a molecular and developmental biologist at the Molecular Pathology Research Institute in Vienna, and collaborators at several institutions asked how sperm proteins might come together during fertilization.
The researchers rely on AlphaFold, a technology that shared the Nobel Prize in Chemistry last week. It uses AI to predict the shape of a protein. With AlphaFold, the team compared four sperm proteins in mammals and fish to a library of about 1,400 other proteins found on the cell surface in zebrafish testes to search for potential partners.
“We wanted to find something that we knew would be in the right place and at the right time,” said Victoria Denek, a postdoctoral researcher in Dr. Pauli’s lab.
Even for Alphafold, this was a challenge. “It was running for two or three weeks,” Dr. Tenek monopolized the campus’s computing resources.
“Others in the company weren’t so happy,” added Dr. Pauli.
Finally, AlphaFold predicted that two originally shared sperm proteins would bind to each other, along with a previously unknown third protein, forming a group of three.
Laboratory experiments confirmed the project’s guess: male zebrafish lacking the newly discovered third protein were as sterile as male mice. Their sperm swam normally but failed to fuse with the egg. The scientists also found biochemical evidence that the three sperm proteins function as a unit in zebrafish and humans.
Many or all vertebrates likely have this same critical joint, Dr. Pauli said.
He described the sperm protein bundle as a kind of key that fits into a lock on an egg cell. In fish, that lock is a protein called Bouncer — perfect, because without it the sperm head can’t enter the egg.
Previous research has also identified a lock molecule in mammalian eggs that binds to one of the three protein bundle proteins. However, oddly enough, the mammal is not a lock bouncer. It is an unrelated protein called Juno.
That means somewhere in history, animals must have evolved different egg proteins to bind the sperm protein bundle. This presents a mystery, Dr. Polly said: The lock has changed, yet somehow, “the key to sperm remains the same.”
“We want to know the answer,” he added.
Amber Krachunas, a reproductive biologist at the University of Delaware who was not involved in the new research, called the new paper “really exciting.”
Earlier this year, a different research team independently used AlphaFold predicted The presence of a single three-protein bundle in mammals. “Having two independent groups come to similar conclusions certainly increases our confidence in the results,” said Dr. Krauchunas.
Still, he said, “there is certainly more work to be done to unravel the mysteries of conception.” For example, some sperm proteins are shared across mammals and fish, but are not part of this bundle; What are they doing?
“This is a fundamental question with very few molecular answers,” said Dr. Pauli. “It’s amazing.”
