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Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
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2015 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, 2267-2279 p.Article in journal (Refereed) Published
Abstract [en]

Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

Place, publisher, year, edition, pages
Cell Press , 2015. Vol. 23, no 12, 2267-2279 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106184DOI: 10.1016/j.str.2015.10.010OAI: oai:DiVA.org:liu-106184DiVA: diva2:714463
Note

The previous status of this article was Manuscript and the original title was Pre-anchoring of Pin1 to unphosphorylated c-Myc in a dynamic complex affects c-Myc stability andactivity.

Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Cancer Foundation; Swedish Child Cancer Foundation; Carl Trygger foundation; LiU Cancer Research Network; Swedish Research Council; NCI [R01s CA129040, CA100855]

Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2017-12-05Bibliographically approved
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.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1584
National Category
Natural Sciences
Identifiers
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)
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Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2014-04-28Bibliographically approved

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Helander, SaraMontecchio, MeriPilstål, RobertKuruvilla, JacobMohammed, JavedCristobal, SusanaLundström, PatrikWallner, BjörnSunnerhagen, Maria

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