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Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility.

Kaoru Nishimura | Elisa Dioguardi | Shunsuke Nishio | Alessandra Villa | Ling Han | Tsukasa Matsuda | Luca Jovine
Nature communications | 2019

Mammalian fertilisation begins when sperm interacts with the egg zona pellucida (ZP), whose ZP1 subunit is important for fertility by covalently cross-linking ZP filaments into a three-dimensional matrix. Like ZP4, a structurally-related component absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Here we report a characterisation of ZP1 proteins carrying mutations from infertile patients, which suggests that, in human, filament cross-linking by ZP1 is crucial to form a stable ZP. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not in human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.

Pubmed ID: 31300655

Associated grants

  • Agency: Vetenskapsrådet (Swedish Research Council), International
    Id: 2016-03999
  • Agency: European Molecular Biology Organization (EMBO), International
    Id: YIP 2009-1931
  • Agency: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)), International
    Id: 260759

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