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<p>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 explore 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 find that this enhanced&#xa0;mechanostability is impaired in the infertility-associated mutant, JunoH177Q. Detailed steered molecular dynamics simulations show how force-dependent structural&#xa0;reorganization of the Izumo1:Juno complex engages previously undiscovered binding conformations to achieve this state of high mechanostability. Overall, this study significantly enhances our understanding of the mechanical underpinnings that regulate human fertilization.</p>

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Multi-state catch bond formed in the Izumo1:Juno complex that initiates human fertilization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Sean Boult,
  • Paulina Pacak,
  • Byeongseon Yang,
  • Haipei Liu,
  • Viola Vogel,
  • Michael A. Nash

摘要

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 explore 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 find that this enhanced mechanostability is impaired in the infertility-associated mutant, JunoH177Q. Detailed steered molecular dynamics simulations show how force-dependent structural reorganization of the Izumo1:Juno complex engages previously undiscovered binding conformations to achieve this state of high mechanostability. Overall, this study significantly enhances our understanding of the mechanical underpinnings that regulate human fertilization.