Structural biology of transcriptional regulation in the c-Myc network
Sammanfattning: The oncogene c-?Myc is overexpressed in many types of human cancers and regulation of c-?Myc expression is crucial in a normal cell. The intrinsically disordered N-?terminal transactivation domain interacts with a wide range of proteins regulating c-?Myc activity. The highly conserved Myc box I region includes residues Thr58 and Ser62, which are involved in the phosphorylation events that control c-?Myc degradation by ubiquitination. Aggressive cell growth, leading to tumor formation, occurs if activated c-? Myc is not degraded by ubiquitination. Such events may be triggered by defects in the regulated network of interactions involving Pin1 and phospho-?dependent kinases.In this thesis, the properties of the intrinsically disordered unphosphorylated c-?Myc1-?88 and its interaction with Bin1 are studied by nuclear magnetic resonance (NMR) spectroscopy and surface plasmon resonance (SPR). Furthermore, the interaction of Myc1-?88 with Pin1 is analyzed in molecular detail, both for unphosphorylated and Ser62 phosphorylated c-?Myc1-?88, providing a first molecular description of a disordered but specific c-?Myc complex. A detailed analysis of the dynamics and structural properties of the transcriptional activator TAF in complex with TBP, both by NMR spectroscopy and crystallography, provides insight into transcriptional regulation and how c-?Myc could interact with TBP. Finally, the structure of a novel N-?terminal domain motif in FKBP25, which we name the Basic Tilted Helix Bundle (BTHB) domain, and its binding to YY1, which also binds c-?Myc, is described. By investigating the structural and dynamic properties of c-?Myc and c-?Myc-?interacting proteins, this thesis thus provides further insight to the molecular basis for c-?Myc functionality in transcriptional regulation.
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