Structural mechanisms and evolution of egg-sperm interactions

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 DESCRIPTION (provided by applicant): The incidence of infertility has increased 4% since the 1980s, with up to 20% cases having no known cause. One of the prevailing hypotheses is incompatibility between cognate egg and sperm proteins; however, very few pairs of interacting reproductive proteins have been identified in any organism. The best model for studying fertilization remains the marine gastropod abalone, where one of the first steps in fertilization involves the interaction between the sperm protein lysin and its egg coat receptor VERL. As a major component of the abalone egg coat, VERL is a giant, fibrous glycoprotein composed of ~22 ZP-N repeats that form intermolecular hydrogen bonds to create the highly stabilized and protective egg coat. Lysin creates a hole in the egg coat by competing for the hydrogen bonds, allowing sperm to pass and fuse with the oocyte. The VERL repeats are homologous to human egg coat proteins, and likely share a similar protein topology. However, the precise structural mechanisms that drive egg coat dissolution remains to be determined. To address this fundamental question in fertilization, two specific aims are proposed using state-of-the-art structural and proteomic approaches. In aim 1, multidimensional NMR will be used to characterize the structural basis of lysin-VERL interactions for three species of abalone. In aim 2, deep mutational scanning will be utilized to explore the specific adaptations acquired by lysin and VERL that permit species specific interactions, and simultaneously test theoretical models of sexual selection. The proposed research is innovative for its combined use of proteomic and structural techniques to characterize the evolutionary history of rapidly evolving reproductive proteins. The results are expected to shed insight into the core mechanisms that mediate egg-sperm interactions in abalone, and provide foundational information towards understanding the more complex mammalian system.