Structural characterization of protein complexes involved in embryogenesis.

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DESCRIPTION (provided by applicant): Birth defects, such as those effecting cardiovascular (e.g. Coarctation of the Aorta), nervous system (e.g. Spina bifida) and craniofacial development (e.g. Cleft Palate) are responsible for roughly 20% of infant deaths in the United States and place an exceeding burden on the health care system amounting to billions of dollars each year. Such defects are often the result of disruptions in embryogenesis, which depends on tight regulation of key pathways including Wnt, Hedgehog, Notch, PAR, and Bone morphogenetic peptide/TGF beta. Many of the protein complexes involved in these pathways however lack detailed molecular characterization, and more still remain to be discovered. Large-scale proteomics efforts focused on embryonic tissues are beginning to systematically identify proteins in vast numbers. Using these data, I propose to develop new methods to structurally and functionally characterize protein complexes associated with embryogenesis. Specifically, I will develop novel computational tools (i) to datamine for proximal interactions (i.e. protein subcomplexes) as well as (ii) to calculate protein stoichiometry. I will then integrate this information to build structural models capable of both characterizing individual complex functions as well as identifying their role in developmental failure. These results will provide a greatly needed mechanistic understanding of the protein complexes associated with embryogenesis and potentially uncover therapeutic targets to treat developmental failures. Moreover, the methods developed here will provide the capability to analyze virtually any biological system and thus should have broad implications for the study of many diseases.