Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex

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Abstract
This study describes the structures of the IZUMO1 protein, found on sperm, and the JUNO protein, found on eggs, and sheds light on their roles in sperm–egg fusion during fertilization. During fertilization in mammals, the sperm-associated protein IZUMO1 recognizes the receptor JUNO at the egg surface, but the structural details of the interactions were previously unknown. In two papers published in this issue of Nature, Halil Aydin et al. and Umeharu Ohto et al. present the first atomic-resolution structures of human IZUMO1 and JUNO in unbound and bound conformations. Aydin et al. describe a boomerang-shaped structure for IZUMO1, and their data suggest that IZUMO1 undergoes a major conformational change on binding with high affinity to JUNO. Ohto et al. report an elongated rod-shaped structure for IZUMO1, comprising a helical bundle IZUMO domain connected by a β-hairpin region to an immunoglobulin-like domain. Mutational studies of the IZUMO1–JUNO interface by both groups reveal the structural determinants required for binding. These results provide data that can inform the development of novel non-hormonal contraceptives and fertility treatments. Fertilization is an essential biological process in sexual reproduction and comprises a series of molecular interactions between the sperm and egg1,2. The fusion of the haploid spermatozoon and oocyte is the culminating event in mammalian fertilization, enabling the creation of a new, genetically distinct diploid organism3,4. The merger of two gametes is achieved through a two-step mechanism in which the sperm protein IZUMO1 on the equatorial segment of the acrosome-reacted sperm recognizes its receptor, JUNO, on the egg surface4,5,6. This recognition is followed by the fusion of the two plasma membranes. IZUMO1 and JUNO proteins are indispensable for fertilization, as constitutive knockdown of either protein results in mice that are healthy but infertile5,6. Despite their central importance in reproductive medicine, the molecular architectures of these proteins and the details of their functional roles in fertilization are not known. Here we present the crystal structures of human IZUMO1 and JUNO in unbound and bound conformations. The human IZUMO1 structure exhibits a distinct boomerang shape and provides structural insights into the IZUMO family of proteins7. 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 insights into the molecular basis of sperm–egg recognition, cross-species fertilization, and the barrier to polyspermy, thereby promising benefits for the rational development of non-hormonal contraceptives and fertility treatments for humans and other mammals.