Naturally Occurring Mechanism Impairs Fertility

A Yale-led research team has discovered how a naturally occurring biological mechanism found in mammals can prevent sperm from interacting with an egg, thus standing in the way of fertilization. The discovery, made in rodent models, offers a new avenue for scientific research to help people struggling with fertility issues, while also opening up a new line of research for contraceptive development. The results of the study appear in the journal Proceedings of the National Academy of Sciences.

Sperm and Egg Recognition and Fusion

“This will have direct implications for infertility and contraception research, particularly immune infertility and immune contraception,” said Steven Tang, assistant professor of molecular biophysics and biochemistry at Yale’s School of Arts and Sciences and corresponding author of the study. In the United States, 9% of men and 11% of women of childbearing age suffer from fertility problems. Some of these problems are due to failures in the proper recognition, attachment, and fusion of sperm and eggs. An important part of the fertility process involves IZUMO1, a protein on the surface of sperm cells, and JUNO, a receptor on the egg cell: the IZUMO1-JUNO connection enables sperm and egg recognition and fusion. One way to suppress this connection is with a sperm antibody called OBF13. This naturally occurring antibody – discovered 40 years ago at Osaka University in Japan – can recognize IZUMO1 and interfere with fertilization. However, the details of this mechanism have been unknown until now.

For the new study, the researchers analyzed the X-ray crystal structure of IZUMO1 when it came into contact with OBF13. The researchers found that OBF13 attaches to sperm in such a way that it reconfigures the way sperm come into contact with an egg. The analysis also identified a high-affinity (tightly binding) variant of OBF13 that is effective at blocking sperm from fertilizing eggs.

In addition, the researchers identified important amino acid sites on JUNO that define its ability to bind to IZUMO1. When accessed, these sites allow it to bind sperm and eggs for fertilization, despite interference from OBF13 or its variant. In this paper, they report the first antibody-antigen complex structure against sperm. The researchers are providing high-resolution information that will lead the way to discovering IZUMO1 regulators, developing lead antibodies and small molecule inhibitors, and supporting drug screening for contraceptive development.