A groundbreaking study led by Yale University researchers has uncovered a naturally occurring biological mechanism that blocks sperm cells from interacting with an egg, preventing fertilization. This discovery, made using rodent models, could open new avenues for fertility treatments and the development of contraceptive therapies. The findings were published in the Proceedings of the National Academy of Sciences.
The research, led by Steven Tang, an assistant professor of molecular biophysics and biochemistry at Yale, sheds light on the underlying mechanisms of infertility and contraception, specifically in relation to immuno-infertility and immuno-contraception. Tang emphasized that this work could significantly impact future treatments for infertility and contraceptive development.
In the United States, approximately 9% of men and 11% of women of reproductive age experience fertility challenges, many of which stem from issues with sperm and egg recognition, adhesion, and fusion. A critical factor in this process is the interaction between IZUMO1, a protein found on sperm, and JUNO, a receptor on the egg. The binding of these two proteins enables the sperm and egg to recognize each other and fuse, which is essential for fertilization.
However, the process can be disrupted by the presence of a sperm antibody known as OBF13. Discovered over four decades ago by researchers at Osaka University in Japan, OBF13 binds to IZUMO1 and impedes sperm-egg fusion, preventing fertilization. Until now, the exact mechanism by which OBF13 interferes with fertilization had remained unclear.
In their study, the research team examined the X-ray crystal structure of IZUMO1 when it interacted with OBF13. They found that OBF13 attaches to sperm in a way that alters how sperm interact with the egg. The researchers also identified a variant of OBF13 that binds more tightly to sperm, significantly blocking the fertilization process.
Additionally, the study revealed crucial amino acid sites on JUNO that enable the receptor to bind with IZUMO1. Even in the presence of OBF13, these sites allow the sperm and egg to connect and undergo fertilization.
“This study reports the first anti-sperm antibody-antigen complex structure,” said Tang. “We provide high-resolution insights that will help discover new IZUMO1 regulators and guide the design of antibodies, small-molecule inhibitors, and drug screening methods for the development of contraceptives.”
Yonggang Lu of Osaka University served as the study’s first author, with Masahito Ikawa, also from Osaka University, contributing as a co-author. The research was supported by the National Institutes of Health, the David Sokal Innovation Award of the Male Contraception Initiative, the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, and the Takeda Science Foundation. The study also benefited from facilities at the SLAC National Accelerator Laboratory, which is supported by the U.S. Department of Energy’s Office of Science.
This discovery provides valuable insights that may lead to improved fertility treatments and the creation of more effective contraceptive methods.
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