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Title: Investigating the structural domains required for activation of the human discoidin domain receptors, DDR1 and DDR2
Author: Noordeen, Nafeesa Alibhai
ISNI:       0000 0001 3448 6916
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2006
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The human discoidin domain receptors (DDRs), DDR1 and DDR2, are a unique subfamily of receptor tyrosine kinase as they bind to and are activated by the extracellular matrix protein collagen. The DDRs are expressed widely and play an important role in cell-matrix interaction, cell adhesion, motility and proliferation. Several different collagen types activate the DDRs, and both DDRs bind only native, triple-helical collagen and not denatured collagen. The DDRs need to be dimerised in order to bind collagen, as shown by studies using soluble extracellular domain (ECD) constructs of DDR1 and DDR2. However, the oligomerisation state of the full-length receptors on the cell surface has not been investigated. In this study, chemical cross-linking analysis and co- immunoprecipitation of FLAG- and MYC-tagged receptors show that full-length DDRs, expressed on the cell surface, exist as preformed oligomers in the absence of ligand. The DDR domains involved in dimerisation were investigated. Both DDR1 and DDR2 are composed of an N-terminal discoidin domain followed by a region of no known sequence homology that is predicted to be folded, named domain X in this study. A transmembrane (TM) domain ensues, followed by a juxtamembrane domain and a C-terminal catalytic tyrosine kinase domain (KD). DDR1 contains an additional region rich in proline and glycine situated between the domain X and the TM domain. Chemical cross-linking analysis and co-immunoprecipitation studies of DDR1 and DDR2 deletion mutants indicate that more than one receptor domain is involved in receptor dimerisation, as the deletion of any one of the above mentioned receptor domains was not sufficient to abolish oligomerisation. Furthermore, the role of the TM domain in DDR dimerisation was investigated. DDR mutants containing mutations to disrupt two potential TM dimerisation motifs, a leucine zipper and a GxxxG motif, were studied. Neither motif was required for DDR dimerisation in the absence of ligand. However, the leucine zipper, but not the GxxxG motif, was found to be required for DDR activation in the presence of collagen I, indicating that upon collagen binding, the DDR TM domains self-assemble, and this interaction occurs via the leucine zipper motif.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available