Fine-scale structure of egg crucial for fertility

If fertility had a shape, this would be it.

Scientists have figured out the exact shape of part of a protein that sits on the outside of the egg and aids in fertilization. The results, which may ultimately lead to new contraceptives and treatments for infertility, appear in the Dec. 4 Nature.

On its quest to fertilize an egg, a sperm cell must first get through the outer layer of the egg. Proteins composing this outer layer — called the zona pellucida — have two major jobs during fertilization. The first is to recognize that a sperm cell is from the correct species, and the second is to tighten into a solid shell that seals off the egg as soon as the first lucky sperm penetrates. This barrier prevents other sperm from fertilizing the egg, an event that would be lethal.

While some key players in the zona pellucida are known, scientists continue to search for clues on how sperm and egg join. “We still don’t understand the molecular nature of the initial interactions between the sperm and the egg,” says researcher Sarah Conner, of the University of Birmingham in England.

A research team led by Luca Jovine at the Karolinska Institute in Huddinge, Sweden aimed to examine a small part of the process in great detail. In mice and humans, each of the key zona pellucida proteins — called ZP2 and ZP3 — has a piece called the ZP-N domain. Mice that lack either of the two key zona pellucida proteins that have the ZP-N domain are completely infertile. The ZP-N domain is required for the initial formation of the coat of proteins around the egg, without which fertilization is impossible. ZP-N may also help proteins “tighten the net” around the egg to prevent another sperm from entering, says Jovine.

Jovine’s team solved the structure of a mouse ZP-N region using a technique called X-ray crystallography, which identifies the three-dimensional location of every atom in a protein. Once the researchers knew the ZP-N region’s shape, they compared it to the structures of other, unrelated proteins. The team found that the type of fold in the ZP-N is a twist on a well-known protein shape called the immunoglobulin domain.

Paul Wassarman, a researcher at Mount Sinai School of Medicine in New York City, calls the new structure data an “extremely important contribution to the area of fertilization.”

And it turns out that the ZP-N region is not just important for fertilization. Solving the ZP-N structure could have “widespread implications,” says Wassarman, who originally identified the key zona pellucida protein ZP3. Hundreds more proteins have shapes similar to the one seen in ZP-N, says Wassarman, including proteins in the brain and some implicated in cancer. But the most immediate task will likely be to use the ZP-N structure data to solve mysteries of conception.

Such applications to human fertility will require much more study. Jovine cautions that knowing the structure of the mouse ZP-N is “just a first step.” But female contraceptives targeted to the zona pellucida proteins on the egg could theoretically prevent any sperm from fertilizing the egg. Such an approach would be much more specific than current hormone-based forms of contraception, says Jovine. These kinds of studies could result not only in a new way to prevent fertilization, but also in new ways to promote conception in cases of infertility.

“There’s going to be a lot of work coming out in the next couple of years,” Wassarman predicts.