What happens when a sperm meets an egg? A research team has made this dynamic visible for the first time. The simulations show how the two germ cells make contact, fuse and repel further sperm. According to this, zinc ions are released after fertilization, which means that a protein on the sperm surface changes and can no longer bind to the surface of the egg cell. With knowledge of these molecular mechanisms, new drugs could now be developed to treat or prevent infertility.
During fertilization, a sperm penetrates an egg cell. This seemingly simple process is highly complex and dynamic at the molecular level. To date, no microscope has been able to image the countless interactions that take place between the proteins involved in the two human germ cells. These tiny movements cannot be clearly recognized even from crystalline protein structures or laboratory experiments. So far, what exactly triggers the fertilization process and what happens shortly before and after the sperm and egg fuse has remained obscure.
Protein contact clears the way
A research team led by Paulina Pacak from the Swiss Federal Institute of Technology (ETH) Zurich has now made the dynamics of these processes visible for the first time. To do this, the researchers used computer simulations on a high-performance computer. In particular, they simulated the interactions between the Juno protein, which sits on the female egg, and the Izumo1 protein on the surface of the male sperm. These proteins create the first physical connection between the two germ cells. In order to create a realistic environment in the computer experiment, the researchers simulated the two proteins for the first time in an aqueous solution, in which the proteins behave differently than without interactions with water molecules.
“The simulations provide a more detailed picture of the dynamics of the interactions,” says senior author Viola Vogel from ETH Zurich. The analyzes showed that the Juno-Izumo1 complex is stabilized by up to 35 short-lived contact points between the two proteins, each lasting less than 50 nanoseconds. This enabled the researchers to show how the contact between sperm and egg that is necessary for fertilization is established. This contact may be supported by folates and folic acids, which bind to the Juno protein. The simulations showed that folate can only get into the binding site of Juno if Juno is also bound to Izumo1.
Zinc ions as “remover”
Pacak and her colleagues then examined how these protein bonds are destabilized again after fusion. Zinc ions (Zn2+) play an important role and are released by the egg immediately after fertilization, as the simulations showed. If these ions are present, Izumo1 bends into a kind of boomerang shape. As a result, Izumo1 can no longer bind to the Juno protein and detaches again, making room for further germ cell fusion. At the same time, the egg cell prevents further sperm from penetrating and causing undesirable development, as the researchers report.
The researchers write that the simulations succeeded in revealing important secrets of fertilization. The discoveries are not only of fundamental interest for structural biology, they also provide detailed approaches for the development of new drugs, say Pacak and her colleagues. The decoded interaction of the Juno and Izumo1 proteins could therefore reveal new ways to develop non-hormonal contraceptives, treat infertility and improve in vitro fertilization technology.
Source: Paulina Pacak (ETH Zurich) et al., Scientific Reports, doi: 10.1038/s41598-023-46835-0