Biophysical analyses of peroxiredoxins and a partner reductase Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/rv042w93r

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  • Peroxiredoxins (Prxs) are dominant peroxide-reducing enzymes with two important roles: they protect all organisms from oxidative damage induced by peroxides, and in eukaryotes, they participate in hydrogen peroxide signaling pathways. This dissertation presents studies aimed at the biophysical characterization of select Prxs and a Prx reductase to elucidate their structure-function relationships. It includes two Chapters containing published (or submitted) review articles and three Chapters describing original research, two of which are published papers. A final conclusions Chapter describes the major contributions of this work and future studies. The first review presents the features of both general Prx structure and those unique to each of the six Prx subfamilies. Analysis of the universal Prx active site leads to the novel insight that the catalytic power stems from activation of both enzyme and substrate. The second review describes structural features that allow floodgate-like Prxs to participate in signaling pathways and also surveys the evidence in support of the three proposed models of Prx involvement in redox-based signaling. Two of the Chapters containing original research explore the Prx structural features associated with peroxide reduction. The first is a published analysis of the structural transition required for catalysis in the Tpx subfamily. The identified importance of the dimer interface during catalytic gymnastics and in binding substrate led to the proposal that Tpxs are obligate dimers. The second study provides structural data supporting the insights on catalytic power presented in Chapter 2. Analysis of a novel structure of human PrxV bound to DTT as well as other structures reveals how the active site stabilizes the transition state of the reaction. This Chapter also proposes diols as a novel class of competitive inhibitors. The third original research Chapter is a published characterization of a Prx reductase, the N-terminal domain of the bacterial AhpF (NTD). NMR and fluorescence measurements show that on a timescale relevant to catalysis, the oxidized form of the NTD is more heterogeneous than the reduced form. It also documents how the two thioredoxin folds that make up the NTD have evolved specialized dynamics properties related to the functional fusion of the two folds.
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