Structural studies of egg-sperm interaction and human hedgehog signaling proteins - Luca Jovine
Species-restricted recognition between egg and sperm at fertilization is one of the most crucial steps of development. However, despite decades of investigation, the molecular mechanism of this essential process remains unknown.
Our group uses mammalian cell expression to overproduce in recombinant form the highly posttranslationally modified molecules that are involved in gamete interaction, for both biochemical and X-ray diffraction studies. During the last few years, we determined crystallographic structures of ZP3, a major glycoprotein component of the specialized extracellular coat of the egg that first contacts sperm at conception. This gave insights into the evolution of egg coat architecture from invertebrates to human, and suggested that a glycan conserved from birds to mammals plays an important role in sperm binding. Ongoing projects aim at characterizing complexes between gamete recognition proteins, with possible future application to the understanding of human infertility and the design of targeted non-hormonal contraceptives.
In parallel with our work on fertilization, we have a long term collaboration on human hedgehog signaling proteins with the group of Prof. Rune Toftgård. Recently we determined the structure of full-length tumor suppressor SUFU, a key regulator of the pathway in mammals. This led to the identification of a large regulatory region of the protein, whose interaction with the Gli family of transcription factors is currently being addressed.
Crystal of ZP3, the conserved vertebrate egg coat protein that first binds sperm at the beginning of fertilization.