Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex.
Fertilization is an essential biological process in sexual reproduction and comprises a series of molecular interactions between the sperm and egg. The fusion of the 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 in which the sperm protein IZUMO1 on the equatorial segment of the acrosome-reacted sperm recognizes its receptor, JUNO, on the egg surface. 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 infertile. 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 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 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.
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Halil
H
Aydin
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Azmiri
A
Sultana
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Sheng
S
Li
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Annoj
A
Thavalingam
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Jeffrey E
JE
Lee
D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004527:Egg Proteins; D005260:Female; D005306:Fertilization; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009865:Oocytes / Q000737:chemistry; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D011956:Receptors, Cell Surface; D013084:Sperm-Ovum Interactions; D013094:Spermatozoa / Q000737:chemistry
D002352:Carrier Proteins; D004527:Egg Proteins; C498176:IZUMO1 protein, human; C548698:IZUMO1R protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface