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

Nat Commun. 2019 Jul 12;10(1):3086. doi: 10.1038/s41467-019-10931-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chickens
  • Crystallography, X-Ray
  • Female
  • Fertilization / physiology
  • Frameshift Mutation
  • Humans
  • Infertility, Female / genetics*
  • Molecular Dynamics Simulation
  • Protein Domains / physiology*
  • Protein Multimerization
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • Sequence Alignment
  • Zona Pellucida / metabolism*
  • Zona Pellucida Glycoproteins / genetics
  • Zona Pellucida Glycoproteins / isolation & purification
  • Zona Pellucida Glycoproteins / metabolism*
  • Zona Pellucida Glycoproteins / ultrastructure


  • Recombinant Proteins
  • ZP1 protein, human
  • ZP4 protein, human
  • Zona Pellucida Glycoproteins