Structure-function relationships in cellular copper control
| dc.contributor.advisor | George, Graham N. | en_US |
| dc.contributor.committeeMember | Nichol, Helen | en_US |
| dc.contributor.committeeMember | Ellis, Thomas | en_US |
| dc.contributor.committeeMember | Blackburn, Ninian J. | en_US |
| dc.contributor.committeeMember | Pickering, Ingrid J. | en_US |
| dc.creator | Zhang, Limei | en_US |
| dc.date.accessioned | 2009-06-04T07:52:16Z | en_US |
| dc.date.accessioned | 2013-01-04T04:34:45Z | |
| dc.date.available | 2010-06-09T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T04:34:45Z | |
| dc.date.created | 2009 | en_US |
| dc.date.issued | 2009 | en_US |
| dc.date.submitted | 2009 | en_US |
| dc.description.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. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-06042009-075216 | en_US |
| dc.language.iso | en_US | en_US |
| dc.subject | density functional theory | en_US |
| dc.subject | X-ray absorption spectroscopy | en_US |
| dc.subject | cellular Cu control | en_US |
| dc.subject | molecular dynamics | en_US |
| dc.subject | metallothionein | en_US |
| dc.subject | Cu chapterone | en_US |
| dc.subject | CsoR | en_US |
| dc.subject | MTF-1 | en_US |
| dc.title | Structure-function relationships in cellular copper control | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Geological Sciences | en_US |
| thesis.degree.discipline | Geological Sciences | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |