Structural and functional studies on human DJ-1 (PARK7), a protein associated with early-onset Parkinson's disease

This thesis includes two parts of my work, one being structural and functional studies on human DJ-1, a protein associated with early-onset Parkinson's disease (Chapter I to III), and the other being structural and functional studies on Toll/interleukin-1 receptor (TIR) domain in signal transduction in innate immunity (Chapter IV to VI).; Parkinson's disease represents the second most common neurodegenerative disorder, and mutations in the DJ-1 gene have been associated with autosomal recessive early-onset Parkinson's disease. The exact biological function of DJ-1 is not known, although it has been implicated in several important biological processes. The thesis begins with an introduction to Parkinson's disease (Chapter I) followed by the studies on human DJ-1 protein with different techniques, including X-ray crystallography, mutagenesis, chromatography, light scattering, and fluorescence-based protease assay (Chapter II). DJ-1 shares a conserved alpha/beta fold among the DJ-1/ThiJ/PfpI superfamily proteins. On the other hand, DJ-1 has its unique properties, such as the C-terminal extra helix, a novel dimerization mode, and potential cysteine protease activity with a novel catalytic diad. In Chapter III, we characterized the possible pathogenic mechanisms of Parkinson's disease by DJ-1 mutations.; Innate immunity represents the sole mechanism of immune protection in invertebrates, provides the first line of host defense against invading pathogens and is a prerequisite for the induction of adaptive immunity in vertebrates. It is regulated by a set of pattern recognition receptors, including Toll-like receptors (TLRs). The intracellular domain of TLRs, named Toll/interleukin-1 receptor domain, is critical for the signaling by serving as a protein-protein interaction module (Chapter IV). To characterize the structural basis of signal transduction by TIR domains, we have initiated structural and functional studies on TIR domains of TLRs and other proteins (Chapter V and VI).