Following activation of inflammatory cells, enhanced bulk transbilayer movement of plasma membrane phospholipids (flip-flop) of scramblase results in profound biological consequences. The appearance of phosphatidylserine in the plasma membrane outer leaflet results in the marked enhancement of coagulation, either appropriate as in hemostasis, or inappropriate as in acute lung injury. Similarly, the appearance of phosphatidylserine markedly enhances complement activation and serves as a signal for the recognition and uptake of apoptotic cells by phagocytes. Furthermore, scramblase activation will result in either release (from the synthesizing cell) or uptake (into target cells) of mediator phospholipids (platelet activating factor (PAF), lysophospholipids, and oxidized phospholipids) or their precursors (delivery of arachidonate to secreted PLA2). Depending on cell type, stimulus, and isoform of the scramblase, it is hypothesized that at least four mechanisms are involved in regulating scramblase activity: a) phosphorylation of scramblase by PKC (e.g. fMLP-stimulated neutrophils or Jurkat cell apoptosis), b) elevation of intracellular calcium in the absence of phosphorylation (e.g. thrombin-stimulated platelets), c) translocation to and from the membrane (fMLP-stimulated neutrophil) and d) cytokine-mediated up-regulation of scramblase expression (interferon alpha treated Raji cells).
The aims of this project are to define the regulation of scramblase by phosphorylation and determine the mechanism(s) by which scramblase enhances transbilayer movement of membrane phospholipids. Integrated biochemical, structural and genetic approaches are described in which the scramblase phosphorylation activity, be identified and the effect of phosphorylation on scramblase activity, particularly with regard to calcium requirement, defined. Similarly, these same integrated approaches will be used to define the mechanism by which scramblase mediates the transbilayer movement of phospholipids, hypothesized to require either self-association or association with other proteins.
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