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

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.