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

Abstract

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 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 where the sperm Izumo1 on the equatorial segment of the acrosome-reacted sperm recognizes its receptor Juno, on the egg surface4–6. 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 infertile5,6. 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 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 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.

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

“…Observed male infertility phenotypes were often associated with disrupted PPIs involved in sperm maturation, migration, zona pellucida binding and sperm-oocyte fusion (1-7). However, little knowledge on mouse testis-specific proteins has been translated into studies on human reproduction (13,55), often due to the absence of human orthologs. For example, examination of testis-specific genes of the ADAM family revealed only six mouse genes with corresponding human orthologs (Adam2, Adam18, Adam21, Adam29, Adam30, Adam32), while twelve genes (Adam1a, Adam1b, Adam3, Adam4, Adam5, Adam6a, Adam6b, Adam24, Adam25, Adam26a, Adam26b, Adam34) did not have human orthologs or were non-coding pseudogenes in humans (56).…”

Pipeline for contraceptive development

“…Several ADAMs proteins form complexes that are required for sperm-zona pellucida or sperm-egg binding (82). Izumo1 is a sperm surface protein that binds to JUNO on the egg leading to sperm-egg fusion (84). Many other potential targets that effect sperm function have been identified.…”

When sperm meets egg

“…However, the details of this interaction have been elusive. In two papers online in Nature, Aydin et al 1 and Ohto et al 2 present the structures of Izumo1, Juno and the two proteins in complex, determined by X-ray crystallography at atomic-level resolution.…”