Cell Surface Receptor Recognition and Membrane Fusion in Mammalian Fertilization

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Project Summary/Abstract Fertilization is an essential biological process that involves cell surface recognition, adhesion, and fusion of haploid sperm and egg to form a new, genetically distinct diploid organism. Surprisingly little is known about how plasma membranes interact and fuse, largely due to the limited availability of mammalian gametes and the technical challenges of capturing transient extracellular interactions. While the gamete membrane fusion machinery remains elusive, it is known that a human immunoglobulin superfamily protein, Izumo1, localizes to the equatorial segment of spermatozoon, where it interacts with an oocyte ligand, Juno, before gamete fusion takes place. To date, Izumo1- Juno is the only essential receptor-ligand pair identified in the pathway. Recent genetic studies in mice have identified additional sperm surface proteins essential for male fertility, but their interactions and regulation have not been defined. To close these major gaps, I have designed a research program around the central hypothesis that gamete surface proteins orchestrate their structural rearrangements and membrane remodeling, leading to gamete fusion. I will test my hypothesis by (1) determining the molecular mechanisms of human Izumo1 self-assembly, (2) characterizing the roles of human Izumo family proteins in membrane adhesion and fusion, and (3) identifying additional receptor-ligand interactions essential for gamete fusion and mammalian fertilization. My multidisciplinary approach leverages high- resolution structural analyses to interrogate the functional organization of known essential gamete surface proteins, and harnesses high-throughput forward genetic screens to explore the interacting networks of additional emerging molecules. Crucially, understanding these interactions will elucidate mechanisms of cell-cell recognition and membrane fusion and reveal essential factors that maintain human fertility and reproductive health. From graduate school, I have extensive training in genetics, cell biology, and membrane biochemistry. During my early postdoctoral work, I honed my skills in structural biology of cell surface receptors and protein engineering of viral membrane fusion machines. I will exploit the excellent research environments in the laboratories of my mentor Dr. Peter Kim and my co-mentor Dr. Chaitan Khosla and at Stanford University. Under the guidance of my outstanding scientific advisory committee, I will obtain training essential to mastering enzymology, germ cell biology, and functional genomics. These research and career-development opportunities will empower me to establish an independent laboratory to study fundamental questions in the mammalian sperm-egg fertilization process at the levels of cell biology, mechanistic biochemistry, and structural biology.