Structure of IZUMO1–JUNO reveals sperm–oocyte recognition during mammalian fertilization

• Published in: Nature (London) Vol. 534; no. 7608; pp. 566 - 569
• Main Authors: Ohto, Umeharu, Ishida, Hanako, Krayukhina, Elena, Uchiyama, Susumu, Inoue, Naokazu, Shimizu, Toshiyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.06.2016; Nature Publishing Group
• Subjects: 631/136; 631/535/1266; Analysis; Binding Sites - genetics; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chemical bonds; Crystal structure; Crystallography, X-Ray; Female; Fertility; Fertilization (Biology); Humanities and Social Sciences; Humans; Immunoglobulins; Immunoglobulins - chemistry; Immunoglobulins - genetics; Immunoglobulins - metabolism; letter; Ligands; Male; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Models, Molecular; multidisciplinary; Mutation; Oocytes; Oocytes - chemistry; Oocytes - metabolism; Protein Binding - genetics; Protein Structure, Tertiary; Proteins; Reproduction; Science; Sexual reproduction; Sperm; Sperm-Ovum Interactions - genetics; Spermatozoa - chemistry; Spermatozoa - metabolism; Vitamin B; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature18596

The structure of the IZUMO1–JUNO complex, crucial for sperm–oocyte interaction during fertilization, is reported, providing a first step towards understanding the mechanics of the interaction. Structure of the human fertilization complex 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 a fundamental process in sexual reproduction, creating a new individual through the combination of male and female gametes 1 , 2 , 3 , 4 . The IZUMO1 sperm membrane protein 5 and its counterpart oocyte receptor JUNO 6 have been identified as essential factors for sperm–oocyte interaction and fusion. However, the mechanism underlying their specific recognition remains poorly defined. Here, we show the crystal structures of human IZUMO1, JUNO and the IZUMO1–JUNO complex, establishing the structural basis for the IZUMO1–JUNO-mediated sperm–oocyte interaction. IZUMO1 exhibits an elongated rod-shaped structure comprised of a helical bundle IZUMO domain and an immunoglobulin-like domain that are each firmly anchored to an intervening β-hairpin region through conserved disulfide bonds. The central β-hairpin region of IZUMO1 provides the main platform for JUNO binding, while the surface located behind the putative JUNO ligand binding pocket is involved in IZUMO1 binding. Structure-based mutagenesis analysis confirms the biological importance of the IZUMO1–JUNO interaction. This structure provides a major step towards elucidating an essential phase of fertilization and it will contribute to the development of new therapeutic interventions for fertility, such as contraceptive agents.