Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex.
Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex.
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DOI：
10.1038/nature18595
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发表时间：
2016-06-23
期刊：
影响因子：
64.8
通讯作者：
Lee JE
中科院分区：
文献类型：
--
作者：
Aydin H;Sultana A;Li S;Thavalingam A;Lee JE
受精是有性生殖中重要的生物过程，包括精子和卵子之间的一系列分子相互作用。单倍体精子和卵母细胞的融合是哺乳动物受精的最终事件，从而能够产生新的遗传独特的二倍体生物体。两个配子的合并是通过两步机制实现的，其中顶体反应精子赤道段上的精子 Izumo1 识别卵子表面的受体 Juno。随后是两个质膜的融合。 Izumo1 和 Juno 蛋白对于受精是不可或缺的，因为 Izumo1 或 Juno 蛋白的组成型敲除会导致小鼠健康但不育。尽管它们在生殖医学中具有核心重要性，但它们在受精中的分子结构和功能细节尚不清楚。在这里，我们展示了人类 Izumo1 和 Juno 的未结合和结合构象的晶体结构。人类 Izumo1 结构表现出独特的回旋镖形状，并为了解 Izumo 蛋白质家族提供了第一个结构见解。人 Izumo1 与 Juno 形成高亲和力复合物，并在与卵表面受体结合后，其 N 末端结构域内发生主要构象变化。我们的研究结果为精卵识别、跨物种受精和多精障碍的分子基础提供了新的见解，从而有望为人类和其他哺乳动物物种的新型非激素避孕药和生育治疗的合理开发带来益处。
Fertilization is an essential biological process in sexual reproduction and comprises a series of molecular interactions between the sperm and egg. The fusion of haploid spermatozoon and oocyte is the culminating event in mammalian fertilization, enabling the creation of a new genetically distinct diploid organism. The merger of two gametes is achieved through a two-step mechanism where the sperm Izumo1 on the equatorial segment of the acrosome-reacted sperm recognizes its receptor Juno, on the egg surface. This is followed by the fusion of two plasma membranes. Izumo1 and Juno proteins are indispensable for fertilization as constitutive knockout of either Izumo1 or Juno result in mice that are healthy but infertile. Despite their central importance in reproductive medicine, the molecular architectures and the details of their functional roles in fertilization are not known. Here, we present the crystal structures of the human Izumo1 and Juno in unbound and bound conformations. The human Izumo1 structure exhibits a distinct boomerang shape and provides the first structural insights into the Izumo family of proteins. Human Izumo1 forms a high-affinity complex with Juno and undergoes a major conformational change within its N-terminal domain upon binding to the egg-surface receptor. Our results provide new insights into the molecular basis of sperm-egg recognition, cross-species fertilization, and barrier to polyspermy, thus promising benefits for the rational development of novel non-hormonal contraceptives and fertility treatments for humans and other species of mammals.