How life begins: Egg, sperm, and a covert team of proteins

Ever wonder about how life starts? Most of us know it has something to do with eggs, sperm, and maybe proteins, but the exact choreography that sees these partners meet and merge has remained somewhat of an enigma.

This fascinating tale is far from over, as researchers utilizing Google’s spectacular AlphaFold technology discovered a surprising new twist.

Egg connecting to sperm

Typically, opposites attract. In this context, you cannot find a pair more diverse than the egg and the sperm.

One is a microscopic champion swimmer, always on the go, while the other is a stationary, voluminous entity, the blueprint for life. Their union forms the bedrock of sexual reproduction, spanning across every species on planet Earth.

The “how” behind this vital fusion has always remained shrouded in mystery, until now. A breakthrough study enlightens us; an interlocked trio of proteins opens the doors to this bond, making the sperm and egg recognize and stick together.

Evidently, this threesome protein bundle is a shared heritage across species – from fish to mammals, and most definitely humans too.

Genesis of sperm, egg and protein

Picture life’s opening scene – a sperm navigating its way to an awaiting egg. The sperm and egg then create a bond, recognizing each other almost instantly.

Within fractions of a second, the head of the sperm plunges into the egg, like stepping through an open doorway. This fusion brings to life a zygote, the starting point of a new creature.

Past studies had identified four “star” proteins on the sperm – with memberships in both mammalian and fish sperm clubs – that are crucial for fertilization. Yet, the exact nature of their teamwork and their modus operandi remained elusive.

Egg, sperm, and proteins

Taking up this challenge, Andrea Pauli, a renowned molecular and developmental biologist at the Research Institute of Molecular Pathology (IMP) in Vienna, alongside her brilliant team, questioned how these sperm proteins might collaborate during the crucial fertilization process.

For this mission, they enlisted the prowess of AlphaFold, an artificial intelligence tech prodigy that bagged the Nobel Prize in Chemistry. AlphaFold can predict the shape of a protein, an essential attribute when dealing with cellular functions.

Armed with this AI, the researchers compared the four sperm proteins common to mammals and fish to about 1,400 other proteins on the zebrafish’s testes’ cell surfaces. They were hoping to find potential allies.

Proteins on the super team

“We wanted to find something that we knew would be at the right place and at the right time,” said Victoria Deneke, a postdoctoral researcher in Dr. Pauli’s lab. It took weeks of analyzing and crunching data to finally predict which proteins might form this super team.

The results were remarkable. AlphaFold proposed two of the original proteins would bind with each other and a third, previously unknown protein. The trio, together, would form the team they were looking for.

Subsequent testing confirmed AlphaFold’s prediction. In both zebrafishes and mice missing the newfound third protein, the males were infertile.

Their sperm, even though mobile, couldn’t fuse with an egg without the protein. Further evidence revealed that this trio of sperm proteins worked as a unit in both zebrafish and humans.

Key and lock mechanism

Think of the trio of proteins as a “key” that opens a “lock” on the egg cell. For fish, this lock is a protein appropriately named ‘Bouncer.’ Without the Bouncer protein, the sperm cannot gain entry into the egg.

Interestingly, though, the mammalian lock in this story is not Bouncer; it’s an unrelated protein named Juno.

This suggests that at some point in our evolutionary journey, different egg proteins evolved to bind with the sperm protein bundle. The mystery that baffles Dr. Pauli’s team is how the lock changed while the key on the sperm remained the same.

An exciting step forward

Amber Krauchunas, a reproductive biologist at the University of Delaware, views this research as exciting and a big step forward.

Earlier in the year, another research group independently used AlphaFold, and they predicted the existence of the same three-protein bundle in mammals. The fact that two groups arrived at the same conclusion significantly boosts confidence in the findings.

Yet, the curtain hasn’t completely lifted on the mystery of egg, sperm, protein and eventual fertilization. Some sperm proteins, known to be common across mammals and fish, are not part of this trio. It raises the question – what roles do they play?

“This is such a fundamental question with so few molecular answers,” Dr. Pauli said. “It’s amazing.” For now, we can relish the fact that we are a bit closer to understanding one of life’s greatest mysteries.

The study is published in the journal Cell.

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