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Helander, Sara
Publications (9 of 9) Show all publications
Tu, W. B., Helander, S., Pilstål, R., Ashley Hickman, K., Lourenco, C., Jurisica, I., . . . Penn, L. Z. (2015). Myc and its interactors take shape. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, 1849(5), 469-483
Open this publication in new window or tab >>Myc and its interactors take shape
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2015 (English)In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1849, no 5, p. 469-483Article, review/survey (Refereed) Published
Abstract [en]

The Myc oncoprotein is a key contributor to the development of many human cancers. As such, understanding its molecular activities and biological functions has been a field of active research since its discovery more than three decades ago. Genome-wide studies have revealed Myc to be a global regulator of gene expression. The identification of its DNA-binding partner protein, Max, launched an area of extensive research into both the protein-protein interactions and protein structure of Myc. In this review, we highlight key insights with respect to Myc interactors and protein structure that contribute to the understanding of Mycs roles in transcriptional regulation and cancer. Structural analyses of Myc show many critical regions with transient structures that mediate protein interactions and biological functions. Interactors, such as Max, TRRAP, and PTEF-b, provide mechanistic insight into Mycs transcriptional activities, while others, such as ubiquitin ligases, regulate the Myc protein itself. It is appreciated that Myc possesses a large interactome, yet the functional relevance of many interactors remains unknown. Here, we discuss future research trends that embrace advances in genome-wide and proteome-wide approaches to systematically elucidate mechanisms of Myc action. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology. (C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Myc; Protein-protein interaction; Protein structure; Transcriptional regulation; Post-translational modification; Cancer
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-118983 (URN)10.1016/j.bbagrm.2014.06.002 (DOI)000354581400002 ()24933113 (PubMedID)
Note

Funding Agencies|Canadian Cancer Society Research Institute [018298, 020276]; Canadian Institutes of Health Research [MOP-275788]; Swedish Cancer Society [13 0736]; Swedish Childhood Cancer Foundation [PROJ12/073]; Swedish Research Council [621-2012-5250]; Swedish e-Science Research Center [VR 621-2012-5270, CTS 12:516]; Ontario Research Fund [GL2-01-030]; Canada Research Chair Program

Available from: 2015-06-08 Created: 2015-06-05 Last updated: 2017-12-04
Helander, S., Montecchio, M., Pilstål, R., Su, Y., Kuruvilla, J., Johansson, M., . . . Sunnerhagen, M. (2015). Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. Structure, 23(12), 2267-2279
Open this publication in new window or tab >>Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
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2015 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, p. 2267-2279Article 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
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106184 (URN)10.1016/j.str.2015.10.010 (DOI)
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: 2018-05-06Bibliographically approved
Niklasson, M., Andrésen, C., Helander, S., Roth, M., Zimdahl Kahlin, A., Lindqvist Appell, M., . . . Lundström, P. (2015). Robust and convenient analysis of protein thermal and chemical stability. Protein Science, 24(12), 2055-2062
Open this publication in new window or tab >>Robust and convenient analysis of protein thermal and chemical stability
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2015 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, no 12, p. 2055-2062Article in journal (Refereed) Published
Abstract [en]

We present the software CDpal that is used to analyze thermal and chemical denaturation data to obtain information on protein stability. The software uses standard assumptions and equations applied to two-state and various types of three-state denaturation models in order to determine thermodynamic parameters. It can analyze denaturation monitored by both circular dichroism and fluorescence spectroscopy and is extremely flexible in terms of input format. Furthermore, it is intuitive and easy to use because of the graphical user interface and extensive documentation. As illustrated by the examples herein, CDpal should be a valuable tool for analysis of protein stability.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
protein stability; thermal denaturation; chemical denaturation; circular dichroism; fluorescence; curve fitting; protein stability software; protein denaturation software
National Category
Chemical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124648 (URN)10.1002/pro.2809 (DOI)000368292000014 ()26402034 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-5136]; LiU Cancer

Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2017-11-30
Helander, S., Montecchio, M., Lemak, A., Farès, C., Almlöf, J., Li, Y., . . . Sunnerhagen, M. (2014). Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1. Biochemical and Biophysical Research Communications - BBRC, 447(1), 26-31
Open this publication in new window or tab >>Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1
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2014 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 447, no 1, p. 26-31Article 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
National Category
Chemical Sciences Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106183 (URN)10.1016/j.bbrc.2014.03.068 (DOI)000335806700005 ()24667607 (PubMedID)
Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2017-12-05Bibliographically approved
Helander, S. (2014). Structural biology of transcriptional regulation in the c-Myc network. (Doctoral dissertation). Linköping: Linköping University Electronic Press
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. p. 70
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)
Opponent
Supervisors
Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2019-11-19Bibliographically approved
Anandapadmanaban, M., Andrésen, C., Helander, S., Ohyama, Y., Siponen, M. I., Lundström, P., . . . Sunnerhagen, M. (2013). High-resolution structure of TBP with TAF1 reveals anchoring patterns in transcriptional regulation. Nature Structural & Molecular Biology, 20(8), 1008-+
Open this publication in new window or tab >>High-resolution structure of TBP with TAF1 reveals anchoring patterns in transcriptional regulation
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2013 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 20, no 8, p. 1008-+Article in journal (Refereed) Published
Abstract [en]

The general transcription factor TFIID provides a regulatory platform for transcription initiation. Here we present the crystal structure (1.97 angstrom) and NMR analysis of yeast TAF1 N-terminal domains TAND1 and TAND2 bound to yeast TBP, together with mutational data. We find that yeast TAF1-TAND1, which in itself acts as a transcriptional activator, binds TBPs concave DNA-binding surface by presenting similar anchor residues to TBP as does Mot1 but from a distinct structural scaffold. Furthermore, we show how TAF1-TAND2 uses an aromatic and acidic anchoring pattern to bind a conserved TBP surface groove traversing the basic helix region, and we find highly similar TBP-binding motifs also presented by the structurally distinct TFIIA, Mot1 and Brf1 proteins. Our identification of these anchoring patterns, which can be easily disrupted or enhanced, provides insight into the competitive multiprotein TBP interplay critical to transcriptional regulation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA, 2013
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-96977 (URN)10.1038/nsmb.2611 (DOI)000322715300016 ()
Note

Funding Agencies|Swedish Research Council|621-2011-6028621-2012-5250621-2012-5136|VINNOVA|P32045-1|Swedish Cancer Foundation|11 0681|Swedish Child Cancer Foundation|PROJ09/092|Forum Scientium Award||Canadian Institutes for Health Research|MT-13611|Japan Society for the Promotion of Science|23370077|Knut and Alice Wallenberg foundation||Canada Research Chair||

Available from: 2013-09-05 Created: 2013-09-02 Last updated: 2017-12-06
Andrésen, C., Helander, S., Lemak, A., Fares, C., Csizmok, V., Carlsson, J., . . . Sunnerhagen, M. (2012). Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding. Nucleic Acids Research, 40(13), 6353-6366
Open this publication in new window or tab >>Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
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2012 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, p. 6353-6366Article 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
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-82076 (URN)10.1093/nar/gks263 (DOI)000306970700051 ()
Note

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: 2017-12-07
Andrésen, C., Anandapadamanaban, M., Helander, S., Fladvad, M., Andersson, K., Kanmert, D., . . . Sunnerhagen, M.Molecular characterization of the interaction between the disordered c-Myc transactivation domain and the TATA-binding protein (TBP).
Open this publication in new window or tab >>Molecular characterization of the interaction between the disordered c-Myc transactivation domain and the TATA-binding protein (TBP)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The proto-oncogene c-myc affects the occurrence, expansion, and evolution of numerous aggressive human cancers, and is often associated with the late-stage and/or poor prognostic disease. Regulation of target gene activity by c-Myc occurs through protein interactions with the c-Myc transactivation domain (TAD) which, in addition to binding the TATA-binding protein (TBP) also recruits a wide variety of co-activators and suppressor proteins. Here, we present a molecular model, based on NMR, X-ray crystallography and SPR measurements, which describes how the c-Myc TAD binds to TBP. Our model contributes to the understanding of how c-Myc can regulate individual genes as well as entire gene programs.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-70833 (URN)
Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2011-09-20Bibliographically approved
Andrésen, C., Helander, S., Lemak, A., Farès, C., Csizmok, V., Carlsson, J., . . . Sunnerhagen, M.Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding.
Open this publication in new window or tab >>Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The crucial role of c-Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of c-Myc function. The transactivation domain 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 c-Myc-1-88, where hierarchical phosphorylation of T58 and S62 regulates activation and destruction of the c-Myc protein. By NMR chemical shift analysis, relaxation measurements and NOE analysis, we show that both the MBI region (residues 45-65) and residues 22-33 are transiently structured regions, conserved also in other members of the Myc family. Binding of Bin1-SH3 to c-Myc-1-88 as assayed by NMR and SPR revealed primary binding to the S62 region, but also a dynamically disordered and multivalent complex in which intrinsic disorder of c-Myc-1-88 was retained while releasing transient intramolecular interactions. Our findings describe a novel mode of regulatory recognition of c-Myc that is in agreement with the increasingly recognized capability of intrinsically disordered regions to efficiently mediate transient interactions with a wide range of targets, with important implications towards understanding the unique multifaceted biological functions of c-Myc.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-70832 (URN)
Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2011-09-20Bibliographically approved
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