Structural biology of transcriptional regulation in the c-Myc network
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 70 p.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1584
IdentifiersURN: urn:nbn:se:liu:diva-106185DOI: 10.3384/diss.diva-106185ISBN: 978-91-7519‐370‐0 (print)OAI: oai:DiVA.org:liu-106185DiVA: diva2:714471
2014-05-23, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 09:15 (English)
Gierasch, Lila M., Professor
Sunnerhagen, Maria, ProfessorLundström, Patrik, Dr.
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