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The diverse functions of the MDM2 oncoprotein in growth control and
tumourigenesis are managed through coordinated regulation of its discrete
domains induced by both extrinsic and intrinsic stimuli. A picture of MDM2 is
immerging where structurally discrete but interdependent functional domains
are linked through changes in conformation. However compelling insights
into how this process is carried out have been hindered by inadequate
information on the structure and conformation of the full-length protein.
The data presented indicates that the C-terminal RING domain of MDM2,
primarily responsible of the E3 ubiquitin ligase activity of the protein, has
other intriguing functions. The binding of ATP within the RING domain,
triggers conformational changes of MDM2 and its main interaction partner –
p53. This in effect promotes efficient binding of the p53 tumour suppressor to
specific DNA promoter sequences. Moreover, results presented in this thesis
demonstrate a novel role for the RING domain of MDM2 in determining the
conformation and activity of its N-terminal hydrophobic cleft, the key target of
anticancer drugs designed to activate the function of p53 tumour suppressor
protein. Specific modulations within the RING domain, affecting Zinc
coordination are synonymous with increased binding affinity of the
hydrophobic pocket to the transactivation domain of p53 resulting in a gain of
MDM2 transrepressor function thus leading to a decrease in p53-dependant
gene expression. ThermoFluor measurements and size exclusion
chromatography show that changes in the RING motif lack an effect on the
overall integrity of the MDM2 protein. The intrinsic fluorescence
measurements manifest that these changes generate long range
conformational transitions that are transmitted through the core/central acidic
domain of MDM2 resulting in allosteric regulation of the N-terminal
hydrophobic pocket. Such RING generated conformational changes result in
the relaxation of the hydrophobic pocket. Additionally, it is shown that the
cooperation between the RING and the hydrophobic cleft in MDM2 has
implications in the efficiency of binding of anticancer drugs such as Nutlin by
MDM2. Cooperation between the RING and hydrophobic domain of MDM2 to
regulate function demonstrates an allosteric relationship and highlights the
need to study MDM2 in a native conformation. In essence the presented data
demonstrates that the complex relationship between different domains of
MDM2 can impact on the efficacy of anticancer drugs directed towards its
hydrophobic pocket
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