Proteolysis plays a role in almost every developmental pathway and normal function of the human organism. Quite often, several related proteases cooperate to drive proteolytic pathways that converge on a significant biologic event, often-used examples being blood coagulation, fibrinolysis, antigen presentation, and apoptosis. The balance of proteolysis is achieved by the presence of specific protease inhibitors. Predominant in this are the serpins, members of an evolutionary related superfamily that are demonstrably responsible for regulating the extracellular pathways of coagulation, fibrinolysis, and complement fixation, and one could call these the """"""""regulating"""""""" serpins. Related to these are serpins that block adventitious proteolysis due to the release of potentially damaging proteases from white blood cells. One can call these the """"""""emergency"""""""" serpins since they are thought to block specific proteases, rather than allowing proteolysis to proceed at a regulated rate. Though there is a great deal known about the regulating and emergency plasma serpins, their mechanism of action is still unknown. Moreover, a more recently recognized group of at least 8 human serpins, functioning inside cells, has appeared in the literature. The function of only three of these is known. This leads to the hypothesis that the existence of a group of protease-inhibitory serpins with unknown targets points to as yet unidentified fundamental proteolytic processes occurring inside cells.
The aims of this proposal are to examine aspects of the inhibitory mechanism of serpins by biochemical and X-ray crystallographic methods, and to use this knowledge to determine the cellular targets of a subset of the recently identified intracellular serpins.
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