卵壳交联的分子基础为 ZP1 相关女性不孕提供了线索。
Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility.
机构信息
Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464-8601, Japan.
出版信息
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.
哺乳动物的受精过程始于精子与卵透明带（ZP）相互作用，ZP1 亚基通过将 ZP 丝共价交联成三维基质对生育能力很重要。与在小鼠中缺失的结构相关的 ZP4 类似，ZP1 被预测含有一个功能未知的 N 端 ZP-N 结构域。在这里，我们报告了对来自不孕患者的 ZP1 突变蛋白的特性进行了研究，这表明在人类中，ZP1 的细丝交联对于形成稳定的 ZP 至关重要。我们将 ZP1 的功能定位到其 ZP-N1 结构域，并确定了来自鸡 ZP1 同源物的 ZP-N1 同源二聚体的晶体结构。这些结果表明，ZP 细丝交联具有高度的可变性，可以通过 ZP1 的岩藻糖基化和潜在的锌火花来调节。此外，我们还表明，ZP4 的 ZP-N1 在鸡中形成非共价同源二聚体，但在人 ZP4 中不形成。综上所述，这些数据表明人类 ZP1 交联是一种有前途的非激素避孕目标。
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