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Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
University of Toronto, Canada .
University of Toronto, Canada .
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2012 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, 6353-6366 p.Article in journal (Refereed) Published
Abstract [en]

The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein. By nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements and NOE analysis, we show that although Myc occupies a very heterogeneous conformational space, we find transiently structured regions in residues 22-33 and in the Myc homology box I (MBI; residues 45-65); both these regions are conserved in other members of the Myc family. Binding of Bin1 to Myc-1-88 as assayed by NMR and surface plasmon resonance (SPR) revealed primary binding to the S62 region in a dynamically disordered and multivalent complex, accompanied by population shifts leading to altered intramolecular conformational dynamics. These findings expand the increasingly recognized concept of intrinsically disordered regions mediating transient interactions to Myc, a key transcriptional regulator of major medical importance, and have important implications for further understanding its multifaceted role in gene regulation.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy C / Oxford University Press , 2012. Vol. 40, no 13, 6353-6366 p.
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-82076DOI: 10.1093/nar/gks263ISI: 000306970700051OAI: diva2:557695

Funding Agencies|VINNOVA||CIHR||Swedish Research Council||Swedish Cancer Foundation||Swedish Child Cancer Foundation||Canadian Cancer Society||Ontario Research Fund|GL2-01-030|NIH Protein Structure Initiative grant|U54 GM094597|Canada Research Chairs Program||Swedish NMR Centre||Knut and Alice Wallenberg Foundation||Linkoping University||

Available from: 2012-09-28 Created: 2012-09-28 Last updated: 2015-05-28
In thesis
1. Structural biology of transcriptional regulation in the c-Myc network
Open this publication in new window or tab >>Structural biology of transcriptional regulation in the c-Myc network
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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
National Category
Natural Sciences
urn:nbn:se:liu:diva-106185 (URN)10.3384/diss.diva-106185 (DOI)978-­91-­7519‐370‐0 (print) (ISBN)
Public defence
2014-05-23, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 09:15 (English)
Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2014-04-28Bibliographically approved

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