The moment when a gliding sperm propels itself headlong toward a gelatinous egg is a moment of sudden change. Inside seconds to minuteschemical changes in the egg membrane and outer coat are enacted for block more sperm that adheres to the oocyte and enters it.
A series of reactions also take place when the sperm and egg recognize each other chemically and then begin to fuse their membranes. But despite the importance of these delicate molecular events, their details have not been completely resolved.
A new study by researchers from ETH Zurich and the Ludwig Maximilian University of Munich in Switzerland now reveals the intricacies of a special protein complex known for its crucial role in the fertilization process.
“It was assumed that the combination of the two proteins (JUNO and IZUMO1) in a complex initiates the process of recognition and adhesion between germ cells, thus allowing their fusion,” Explain Paulina Pacak, bioinformatician at ETH Zurich and first author of the study.
This interaction of JUNO, which is found on the outer membrane of the female egg, and IZUMO1, which is found on the surface of the male sperm, is the first known physical link between two newly fusing sex cells.
However, efforts to develop small molecular inhibitors of JUNO-IZUMO1 binding, as a potential contraceptive, have not yielded much success, so researchers suspect there may be more molecular interactions than we know.
Techniques commonly used to discover the structure of individual proteins and protein complexes, such as cryo-electron microscopy and protein crystallographyThey also involve flash-freezing proteins or crystallizing them, meaning they only produce a static image of those protein structures and cannot capture their dynamic interactions.
But inside cells, proteins are constantly being made and folded into shape, floating in a watery mixture of cytoplasmbond and separate from their partners and recycle.
So Pacak and his colleagues used a Swiss supercomputer to simulate the interactions between JUNO and IZUMO1 in water, thus more closely resembling their natural forms in cells.
Each simulation lasted only 200 nanoseconds each, but they showed that the JUNO-IZUMO1 complex is initially stabilized by a series of weak, short-lived compounds. non-covalent interactions between protein molecules.
These contacts lasted less than 50 nanoseconds each, and understanding what happens when they are interrupted, either by other molecules or by mutations, could provide insights into contraceptives and infertility, according to the researchers. suggest.
Next, Pacak and his colleagues simulated how zinc ions could destabilize the more durable bonds that hold the JUNO-IZUMO1 complex together.
Minutes after the sperm and egg unite, the fertilized egg releases a flood of charged zinc atoms that are believed to prevent other sperm from entering the egg hardening its outer shell.
Simulations showed that the presence of zinc ions folded IZUMO1 into a boomerang shape, so it could no longer bind firmly to JUNO. This suggests that the release of zinc from the egg could also make it more difficult for approaching sperm to attach.
While these are just computer simulations based on protein sequences and shapes, the findings provide a new look at the first moments of fertilization.
“We can only discover something like this with the help of simulations,” says Viola Vogel, biophysicist at ETH Zurich and lead author.
“The results we get from them would hardly be possible based on the static crystal structures of the proteins.”
The study has been published in Scientific reports.