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  Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding

Andresen, C., Helander, S., Lemark, A., Farès, C., Csizmok, V., Carlsson, J., et al. (2012). Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding. Nucleic Acids Research, 40(13), 6353-6366.

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Andresen, Cecilia1, Author
Helander, Sara1, Author
Lemark, Alexander2, 3, 4, Author
Farès, Christophe2, 3, 4, 5, Author
Csizmok, Veronika6, Author
Carlsson, Jonas1, Author
Penn, Linda-Z.2, 4, Author
Forman-Kay, Julie D.6, 7, Author
Arrowsmith, Cheryl H.2, 3, 4, Author
Lundström, Patrik1, Author
Sunnerhagen, Maria1, Author
Affiliations:
1Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, SE-58183 Linköping, Sweden, ou_persistent22              
2Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada, ou_persistent22              
3The Northeast Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada, ou_persistent22              
4Ontario Cancer Institute, Toronto, ON M4X 1K9, Canada, ou_persistent22              
5Max Planck Institute for Coal Research, 45470 Mülheim and der Ruhr, Germany , ou_persistent22              
6Molecular Structure and Function Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada, ou_persistent22              
7Department of Biochemistry, University of Toronto, 45470 MülheToronto, ON M5S 1A8, Canada, ou_persistent22              

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 Abstract: 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.

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 Dates: 2012
 Publication Status: Issued
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Title: Nucleic Acids Research
  Other : Nucleic Acids Res.
Source Genre: Journal
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Pages: - Volume / Issue: 40 (13) Sequence Number: - Start / End Page: 6353 - 6366 Identifier: ISSN: 0301-5610
DOI: 10.1093/nar/gks263
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000262810