Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
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DOI：
10.1038/s41467-019-10931-5
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发表时间：
2019-07-12
影响因子：
16.6
通讯作者：
Jovine, Luca
中科院分区：
文献类型：
--
作者：
Nishimura, Kaoru;Dioguardi, Elisa;Jovine, Luca
哺乳动物受精开始于精子与卵透明质酸（ZP）相互作用，其ZP 1亚基通过共价交联ZP细丝进入三维基质对生育力非常重要。像ZP 4一样，ZP 1是一种在小鼠中不存在的结构相关成分，预计含有一个功能未知的N-末端ZP-N结构域。在这里，我们报告的ZP 1蛋白携带不育患者的突变，这表明，在人类中，细丝交联ZP 1是至关重要的，形成一个稳定的ZP的特征。我们将ZP 1的功能映射到其ZP-N1结构域，并从ZP 1的鸡同源物中确定ZP-N1同源二聚体的晶体结构。这些揭示了ZP细丝交联是高度可塑的，并且可以通过ZP 1岩藻糖基化和潜在的锌火花来调节。此外，我们发现ZP 4 ZP-N1在鸡中形成非共价同源二聚体，但在人中不形成。总之，这些数据将人ZP 1交联确定为非激素避孕的有希望的靶点。
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.