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        Structure-function relationships in cellular copper control

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        lzhangThesis.pdf (5.004Mb)
        Date
        2009
        Author
        Zhang, Limei
        Type
        Thesis
        Degree Level
        Doctoral
        Abstract
        X-ray absorption spectroscopy and computational chemistry have been used to probe the structure of biomolecules involved in cellular copper homeostasis. X-ray absorption spectroscopy shows that copper chaperones involved in cytochrome c oxidase assembly bind Cu(I) with trigonal coordination environments in poly-copper thiolate clusters, but the number of coppers in these clusters remains unclear. X-ray absorption spectroscopy of the metal-sensing transcription factor-1 from Drosophila melanogaster and metallothionein from Saccharomyces cerevisiae with stoichiometries of four or less shows a tetracopper cluster in an all-or-none manner in these molecules. These results suggest that cooperative binding of copper to form tetracopper clusters may be a common mechanism employed by copper control molecules. The active site structure of the novel copper-sensitive repressor CsoR in Mycobacterium tuberculosis binds copper in a trigonal coordination geometry with two sulfur and one nitrogen donors according to X-ray absorption spectroscopy results. Molecular dynamics simulations of both apo- and Cu-bound CsoR reveal local conformational changes in CsoR upon copper binding, which suggests multiple possible mechanisms of Cu-dependent transcriptional regulation by CsoR. Finally, X-ray absorption spectroscopy and X-ray fluorescence imaging have been used to understand the molecular basis of a promisng new treatment for Wilson’s disease (a genetic disorder of Cu homeostasis) using tetrathiomolybdate. Overall, the results presented provide an essential structural basis for understanding copper homeostasis in living cells.
        Degree
        Doctor of Philosophy (Ph.D.)
        Department
        Geological Sciences
        Program
        Geological Sciences
        Supervisor
        George, Graham N.
        Committee
        Nichol, Helen; Ellis, Thomas; Blackburn, Ninian J.; Pickering, Ingrid J.
        Copyright Date
        2009
        URI
        http://hdl.handle.net/10388/etd-06042009-075216
        Subject
        density functional theory
        X-ray absorption spectroscopy
        cellular Cu control
        molecular dynamics
        metallothionein
        Cu chapterone
        CsoR
        MTF-1
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