Chemotaxis, the ability of a cell to change its motility as a response to environmental stimuli, belongs to the most important signal transduction mechanisms in life. Evolution has created a plethora of different molecular mechanisms to enable cells to react appropriately to extracellular changes. In this thesis, chemotactic signal transduction pathways in bacteria, in particular two component signalling in R. sphaeroides, and eukaryotes, in particular human axon guidance, are studied by means of X-ray crystallography complemented with biophysical, biochemical and cellular studies. Two-component signal transduction in bacteria is one of the most abundant signalling pathways in biology. Here the determinants for specificity for a crucial sensor kinase-response regulator interaction are presented and used to design novel, synthetic two-component pairs. The activation mechanism of response regulators has been extensively studied and a model for activation that crucially involves a Thr and a Tyr residue has been widely accepted in the field. In this thesis, two structures of a response regulator from R. sphaeroides are presented and together with biophysical and cellular assays suggest a novel paradigm for response regulator activation. Axon guidance is an essential process in human development and relies crucially on chemotaxis. Two signalling pathways, the plexin-semaphorin and the Rgm-Neogenin pathway are studied extensively in this work. Structures of the intracellular region of Plexin-B1 provide an elegant mechanism explaining how ligand binding events on the extracellular and intracellular side can be integrated into a single signalling output. The study of RgmB in complex with its receptor Neogenin provides the first structural insight into the important family of repulsive guidance molecules and explains their role in the disease juvenile hemachromatosis. In summary, this work provides insights into a plethora of chemotactic pathways and extends our current knowledge of these important mechanisms significantly.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:556216 |
| Date | January 2011 |
| Creators | Bell, Christian H. |
| Contributors | Armitage, Judith P. ; Jones, E. Yvonne |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:94441e35-6b9a-4af9-a113-097e2c5da900 |
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