The complement system, as integral part of innate immunity, is an important mediator between inflammatory and homeostatic processes, and participates in the clearance of debris and the defense against microbes. Moreover, its involvement in inflammatory, immune, hematological, age-related, and biomaterial-induced disorders, and its upstream position in inflammation, render complement an interesting target for therapeutic intervention. The balance between activation and regulation of alternative complement pathway (AP), and its central protein component C3, is often what tips the scale between rapid elimination of danger and inapt attack of host cells. Furthermore, human pathogens employ AP inhibition as immune escape strategy. Molecular insight into the processes that shape the activity of C3 therefore has important implications for understanding the role of complement in health, disease and infection, and for the development of complement therapeutics. Based on accomplishments that produced seminal structures and revealed mechanisms of C3-mediated complement activity, this proposal aims at the molecular description of components/events that shape initiation and regulation of the AP and opsonic signaling. The dynamic conversion of C3 to its hydrolytically activated form C3(H2O) will be studied by a combination of structural, biochemical and biophysical methods to reveal its structure and reactivity towards activators and regulators. Careful comparison with C3b as the driving molecule of AP amplification will define determinants of AP activation and provide insight into triggering processes that contribute to inflammatory complications caused by biomaterials or blood oxygenation. Surface opsonization is a direct result of AP amplification and drives phagocytosis and stimulation of adaptive immune responses. In contrast to C3b, the molecular features of the versatile opsonin iC3b that binds to five complement receptors (CR) are still insufficiently described. Structural characterization of iC3b and exploration of its CR recognition pattern will provide important information about the factors that define selectivity and activity ~ the integrin receptor CR3 is of particular interest due to its importance in innate immunity and potential as drug target. Novel cellular assays will extend the study of opsonic signaling at the cellular level and may emerge as tools for drug screening and phagocytic monitoring. Finally, key determinants of physiological AP regulation on host cells will be defined by structural and functional studies of 'regulators of complement activation'(RCA) and microbial mimics thereof. Due to their structural modularity and high AP-directed potency, RCA are considered promising templates for complement inhibitors. Supported on the insight on RCA activity and opsonin specificity as elucidated in this proposal, surface-targeted RCA-based inhibitors will be engineered and evaluated in human and mouse models of complement-mediated disease. One candidate already showed high promise in a model of paroxysmal nocturnal hemoglobinuria, in which it largely surpassed other inhibitors. The proposed studies therefore have high impact for immunology, biomedicine, and drug discovery.
Here we provide molecular insight into activation, regulation and signaling of a central pillar of innate immunity, the human complement system, by resolving the structures and functional mechanisms of several key proteins with direct implications for immunology and biomedicine. In view of the strong involvement of complement in inflammatory, immune, and age-related diseases, a particular focus is set on resolving molecular disease associations and the development of a novel class of potent complement inhibitors based on a promising candidate protein.
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