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Allosteric regulation of proteins by reversible ligand binding is essential for regulation of fundamental biological processes. The mechanism by which a binding event alters the function of a distant site in a protein is only poorly understood. In this thesis, I use the Tetracycline Repressor (TetR) as a model system to study ligand induced allostery. The transcription of genes encoding the resistance to the antibiotic, tetracycline (Tc), is repressed by TetR, which is a homodimeric alpha-helical protein possessing a small N-terminal DNA binding domain (DNB domain) and a larger C-terminal tetracycline binding and dimerization domain (TBD domain). Based on previous structural and thermodynamic studies, the DNB domains are thought to exist in two stable, distinct conformations. One conformation is able to bind the Tc resistance operator sequence (tetO) with high affinity, while the other, which is induced by Tc binding, binds very weakly. While most previous studies on TetR have focused on the effects of Tc binding on the DNB domain conformation, here I have investigated the role of the DNB domain in modulating Tc binding. By introducing destabilizing mutations into the DNB domain I ascertained that the conformation and stability of the DNB domain plays an important role in determining Tc binding affinity. I also discovered that in the absence of ligand, the DNB domain exists in an unstable and flexible state with respect to the TBD domain. However, Tc binding to the TBD domain stabilizes the DNB domain, causing it to fold cooperatively with the TBD domain. I have discovered that the behavior of previously isolated non-inducible mutants is caused by the inability of Tc to stabilize the DNB domain in these mutants. Furthermore, reverse TetR mutants, which bind DNA better in the presence of Tc have an unfolded DNB domain that is only partially stabilized by Tc binding. My work suggests a new comprehensive, Tc induced stabilization and domain cooperativity model that can describe the mechanism of allostery in TetR and previously unexplainable mutants. A practical outcome of this research is the creation of a Tc induced folding switch that can be exploited to control the in vivo degradation of a protein of interest.

Doctor of Philosophy / In this thesis an examination is made of the vibro-replacement technique for the stabilisation of cohesive soils. Improvement is achieved by the formation of stiffer columns of granular material within the soil deposit using a large cylindrical vibrator referred to as a vibroflot. Granular piles (also termed stone columns) are used either singly or in small groups to supoort isolated footings or large numbers are installed in a regular array to support widespread loads. Each of these modes of application are investigated.

Thesis (M.S.)--Oregon State University, 1988. / Typescript (photocopy). Includes bibliographical references (leaves 102-106). Also available on the World Wide Web.

Thesis (Ph. D.)--University of New South Wales, 2003. / Also available online.

Thesis (M. P. A.)--Texas State University-San Marcos, 2005. / "Spring 2005." "Fall 2006"--Spine. Includes bibliographical references (leaves 66-73).

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1991. / Vita. Abstract. Includes bibliographical references (leaves 191-196). Also available via the Internet

Thesis (M.A.)--University of Florida, 2001. / Title from title page of source document. Document formatted into pages; contains viii, 103 p.; also contains graphics. Includes vita. Includes bibliographical references.

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains viii, 91 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 63-64).

Thesis (M. Sc.)--University of Hong Kong, 2002. / Also available in print.