Figure 6: Schematic model for the IZUMO1-JUNO interaction.

In gamete recognition, JUNO first binds to monomeric IZUMO1. By the weak, but specific interaction, an increased amount of JUNO gradually gathers to the attached site of the spermatozoon, which also increases the chance of IZUMO1 self-collision, to induce its dimerization (open dimer form) by depletion association. By the action of PDI-related protein, in the tight binding phase, IZUMO1 bends the entire structure towards the sperm membrane side by a thiol-disulfide exchange reaction. In particular, the N terminal of IZUMO1 (Asp5-Leu113) is folded on to the interior side of the molecule to form a closed dimer. The molecule no longer binds to JUNO and instead binds to a putative oocyte receptor. Presumably, the free energy change by the binding could be close to the level to overcome the charge repulsion of the two phospholipid bilayers. On the other hand, in the case of cells without JUNO, dimeric IZUMO1 could be formed by the presence of IZUMO1 in the juxtaposing membrane probably by the principle of exclusion volume-induced self-association of IZUMO1. However, this structure conversion is incomplete unlike the closed form, which is triggered by JUNO, so that Mab18 or JUNO-FC remains able to bind.