Researchers have uncovered how a naturally occurring biological mechanism is able to prevent sperm cells from interacting with an egg, preventing fertilization.
The discovery, found in rodent models, offers a new path for scientific research to help people with fertility issues, while also opening a new line of study for developing contraceptive therapies.
The findings appear in the journal .
“This will have direct implications for infertility and contraception research, especially immuno-infertility and immuno-contraception,” says Steven Tang, an assistant professor of molecular biophysics and biochemistry at Yale University and corresponding author of the study.
In the United States, 9% of men and 11% of women of reproductive age experience fertility problems. Some of these problems stem from failures in the proper recognition, adhesion, and fusion of sperm and an egg. A key part of the process involves IZUMO1, a protein on the surface of sperm cells, and JUNO, a receptor on the egg. The IZUMO1-JUNO connection enables sperm and egg recognition and fusion.
One way that the connection can be thwarted is via a sperm antibody called OBF13. This naturally occurring antibody was discovered 40 years ago at Osaka University in Japan, and it can recognize IZUMO1 and disrupt fertilization. But until now, the specifics of this mechanism were unknown.
For the study, the researchers analyzed the X-ray crystal structure of IZUMO1 as it came in contact with OBF13. The researchers found that OBF13 attaches itself 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 bonding) variant of OBF13 that potently blocks egg-sperm fertilization.
In addition, the researchers identified key amino acid sites on JUNO that define its ability to bind with IZUMO1. When accessed, these sites are able to bind sperm and egg for fertilization despite interference from OBF13 or its variant.
“In this work, we are reporting the first anti-sperm antibody-antigen complex structure,” Tang says.
“We provide high-resolution information that will open avenues for discovering IZUMO1 regulators, guide antibody and small-molecule inhibitor design, and support drug screening for contraceptive development.”
Additional authors are from Osaka University.
Support for the work came, in part, from the National Institutes of Health, a David Sokal Innovation Award of Male Contraception Initiative, the Japan Society for the Promotion of 糖心视频, the Japan Agency for Medical Research and Development, and a grant from the Takeda 糖心视频 Foundation. The researchers also made use of facilities at the SLAC National Accelerator Laboratory in California, which is supported by the US Department of Energy’s Office of 糖心视频.
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