The goal of this proposal is to characterize the molecular interactions between prostaglandin-H-synthases (PGHS-1 and PGHS-2) with Nucleobindin (Nuc) in order to identify the structural events that are responsible for functional changes in the PGHSs. PGHS isoenzymes, which are integral membrane, heme containing proteins, convert arachidonic acid and O2 to prostaglandin H2 in the committed step of prostaglandin biosynthesis. Both PGHS-1 and PGHS-2 are pharmacologically important as targets of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). The basis for the existence of two PGHS isoenzymes is not known. Although PGHS-1 and PGHS-2 share similar structure and catalytic properties, the isoenzymes have different expression patterns and biological roles. These unique biological functions may depend on PGHSs interaction with proteins that differentially change the catalytic properties of the isoenzymes. Nuc, a 55 kDa transcription factor-like protein, has been identified as a PGHS-interacting protein using the yeast 2 hybrid system. Nuc is associated with pathogenesis of systemic lupus erythematosis (SLE) and causes thymic apoptosis when injected into normal mice. We hypothesize that the interaction of Nuc with PGHSs cause structural changes resulting in functional modifications. To identify the molecular interactions between PGHSs and Nuc and the structural changes in PGHSs associated with the binding of Nuc, the crystal structures of Nuc, and the complexes between PGHS-1:Nuc and PGHS-2:Nuc will be determined.
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