By harnessing the power of structural biology, our laboratory has started to shed light on the molecular recognition events that underlie the origin of a new life.
The first interaction between gametes happens when sperm contacts the surface of the egg coat, called zona pellucida (ZP) in mammals and vitelline envelope (VE) in non-mammals. This is followed by a second recognition event that triggers fusion of the gametes after sperm has penetrated the VE/ZP and contacted the plasma membrane of the oocyte.
By determining 3D structures of ZP2 and ZP3 (major egg coat components that have long been implicated in sperm binding) as well as structurally characterising Juno and Izumo (counterpart proteins on egg and sperm whose interaction is required for gamete fusion), our group has yielded the first atomic-resolution information on molecules essential for both steps of fertilisation in mammals. By also solving structures of mollusc sperm receptor VERL in complex with its binding partner on sperm, protein lysin (figure), we provided a first example of how gametes contact each other at the very beginning of fertilisation and revealed that - despite being separated by 600 million years of evolution - invertebrate and vertebrate egg coat proteins use the same basic molecular architecture to interact with sperm.
In parallel with these studies, our group is also investigating a family of biomedically important human proteins – such as urinary Tamm-Horsfall protein/uromodulin (UMOD) and endothelial glycoprotein endoglin (ENG)/CD105 – that are similar in structure to fertilisation molecules but which perform completely different functions in the body. While our work on fertilisation proteins has important implications for both understanding human infertility and informing the future development of targeted non-hormonal contraceptives, X-ray crystallographic and cryo-EM studies on UMOD, ENG and related proteins allowed us to interpret a large number of human mutations linked to severe pathologies, such as urinary and vascular diseases, non-syndromic deafness and cancer. At the same time, our studies of UMOD and structurally similar human glycoprotein GP2 recently revealed how these molecules counteract bacterial infections in the urinary tract and gastrointestinal system, respectively.