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Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1
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.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Canada.
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2014 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 447, no 1, 26-31 p.Article in journal (Refereed) Published
Abstract [en]

In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.

Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 447, no 1, 26-31 p.
National Category
Chemical Sciences Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106183DOI: 10.1016/j.bbrc.2014.03.068ISI: 000335806700005PubMedID: 24667607OAI: oai:DiVA.org:liu-106183DiVA: diva2:714457
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)9789175193700 (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: 2017-12-15Bibliographically approved

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Helander, SaraMontecchio, MeriSunnerhagen, Maria

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