Structural highlights
9mym is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Method: | X-ray diffraction, Resolution 1.843Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
IZUM1_MOUSE Essential sperm cell-surface protein required for fertilization by acting as a ligand for IZUMO1R/JUNO receptor on egg. The IZUMO1:IZUMO1R/JUNO interaction is a necessary adhesion event between sperm and egg that is required for fertilization but is not sufficient for cell fusion. The ligand-receptor interaction probably does not act as a membrane 'fusogen'.[1] [2]
Publication Abstract from PubMed
Sperm IZUMO1 binds to egg JUNO, and this interaction is essential for mammalian fertilization. Isolated from a female mouse immunized with syngeneic sperm, the antisperm antibody OBF13 recognizes IZUMO1 and inhibits murine fertilization. How OBF13 interferes with sperm-egg interactions was unknown. Here, we present the X-ray crystal structure of IZUMO1 in complex with OBF13. OBF13 binds to the apex of the four-helix domain of IZUMO1, distant from the JUNO-binding site. Our crystal structure of OBF13-bound IZUMO1 resembles apo-IZUMO1 and differs from the structure of IZUMO1 in complex with JUNO. We identify that OBF13 carries a low level of somatic hypermutation, and through deep mutational scanning, we engineer an affinity-enhanced OBF13 variant. This OBF13 variant single-chain fragment variable decreases the apparent affinity of IZUMO1 for membrane-bound murine JUNO and blocks the binding of acrosome-reacted sperm to eggs, thereby preventing fertilization. We propose allostery between the OBF13 epitope and the JUNO-binding site. OBF13 inhibits a conformational change in IZUMO1, preventing fusion-competent sperm from adhering to murine eggs during fertilization. Surprisingly, murine IZUMO1 binds to hamster JUNO with an affinity ~20-fold higher than to murine JUNO. The decreased affinity caused by OBF13 of murine IZUMO1 for hamster JUNO is sufficient for murine sperm to bind to and fuse with hamster eggs. Our studies provide a structural and mechanistic framework for species-specific, allosteric inhibition of IZUMO1 by a naturally occurring antisperm antibody and offer insights into the development of immunocontraceptives.
Allosteric inhibition of the IZUMO1-JUNO fertilization complex by the naturally occurring antisperm antibody OBF13.,Lu Y, Ikawa M, Tang S Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2425952122. doi: , 10.1073/pnas.2425952122. Epub 2025 Mar 5. PMID:40042902[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Inoue N, Ikawa M, Isotani A, Okabe M. The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature. 2005 Mar 10;434(7030):234-8. PMID:15759005 doi:http://dx.doi.org/10.1038/nature03362
- ↑ Bianchi E, Doe B, Goulding D, Wright GJ. Juno is the egg Izumo receptor and is essential for mammalian fertilization. Nature. 2014 Apr 24;508(7497):483-7. doi: 10.1038/nature13203. Epub 2014 Apr 16. PMID:24739963 doi:http://dx.doi.org/10.1038/nature13203
- ↑ Lu Y, Ikawa M, Tang S. Allosteric inhibition of the IZUMO1-JUNO fertilization complex by the naturally occurring antisperm antibody OBF13. Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2425952122. PMID:40042902 doi:10.1073/pnas.2425952122
