Force-dependent Reorganization and Mechanostability of the Izumo1:Juno Complex Involved in Human Fertilization

Izumo1:Juno-mediated adhesion between sperm and egg cells is essential for mammalian sexual reproduction. However, conventional biophysical and structural approaches have provided only limited functional insights. Using atomic force microscopy-based single- molecule force spectroscopy and all-atom steered molecular dynamic simulations, we explored the role of mechanical forces in regulating the human Izumo1:Juno complex. Our findings reveal a multi-state catch bond capable of withstanding forces up to 600 pN- mechanostability rarely observed among eukaryotic protein complexes. We further found that this mechanostability was impaired in the infertility-associated mutant, JunoH177Q. Detailed steered molecular dynamics simulations show how force-dependent reorganization of the Izumo1:Juno complex engages new binding conformations to achieve this state of high mechanostability. Overall, this study significantly enhances our understanding of the mechanical underpinnings that regulate human fertilization.