Membrane Protein Effectors of Pathogen Interactions With Host

SUMMARY Membrane protein effectors of pathogen interactions with host. The goal of this project is to develop a framework for understanding the way in which the human host defenses interact with microbial pathogens and age-related stressors. Many pathogens have evolved strategies to evade innate immunity by recruiting complement regulatory factors onto the microbial cell surface. Moreover, the ectopic deposits that form in age- related macular degeneration (AMD) and Alzheimer's disease (AD) are also rich in blood proteins involved in innate immunity. Despite the biomedical importance of these processes, mechanistic knowledge is limited. This research project is designed to address this knowledge gap. We focus on determining the structural basis for two central interactions of human blood proteins involved in immunity, hemostasis and cell adhesion and cell migration: (1) interactions with outer membrane proteins from the bacterial pathogen Yersinia pestis that are important for pathogenesis, and (2) interactions with lipids and biominerals that are relevant to the formation of pathological deposits associated with AMD and AD. Proteins in these highly heterogenous environments play central roles in human health but are highly under-represented in the scientific knowledge base. We aim to bridge this fundamental knowledge gap. Addressing these problems is important for advancing comprehensive knowledge of the disease process and for developing diagnostic, preventive, and therapeutic approaches. The research strategy is multidisciplinary. It relies significantly on structural biology techniques, particularly solution NMR and solid-state NMR. 1