Activator Protein-1: redox switch controlling structure and DNA-binding
Abstract
The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-binding regions in both FosB and JunD even in absence DNA. However, while JunD is competent to bind DNA, the FosB bZIP domain must undergo a large conformational rearrangement that is controlled by a ‘redox switch’ centered on an inter-molecular disulfide bond. Solution studies confirm that FosB/JunD cannot undergo structural transition and bind DNA when the redox-switch is in the ‘OFF’ state, and show that the mid-point redox potential of the redox switch affords it sensitivity to cellular redox homeostasis. The molecular and structural studies presented here thus reveal the mechanism underlying redox-regulation of AP-1 Fos/Jun transcription factors and provide structural insight for therapeutic interventions targeting AP-1 proteins.
- Authors:
-
- Texas A & M Univ. at Galveston, TX (United States)
- Icahn School of Medicine at Mount Sinai, New York, NY (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1409105
- Grant/Contract Number:
- R01 DA040621
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nucleic Acids Research
- Additional Journal Information:
- Journal Volume: 45; Journal Issue: 19; Journal ID: ISSN 0305-1048
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Yin, Zhou, Machius, Mischa, Nestler, Eric J., and Rudenko, Gabby. Activator Protein-1: redox switch controlling structure and DNA-binding. United States: N. p., 2017.
Web. doi:10.1093/nar/gkx795.
Yin, Zhou, Machius, Mischa, Nestler, Eric J., & Rudenko, Gabby. Activator Protein-1: redox switch controlling structure and DNA-binding. United States. https://doi.org/10.1093/nar/gkx795
Yin, Zhou, Machius, Mischa, Nestler, Eric J., and Rudenko, Gabby. Thu .
"Activator Protein-1: redox switch controlling structure and DNA-binding". United States. https://doi.org/10.1093/nar/gkx795. https://www.osti.gov/servlets/purl/1409105.
@article{osti_1409105,
title = {Activator Protein-1: redox switch controlling structure and DNA-binding},
author = {Yin, Zhou and Machius, Mischa and Nestler, Eric J. and Rudenko, Gabby},
abstractNote = {The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-binding regions in both FosB and JunD even in absence DNA. However, while JunD is competent to bind DNA, the FosB bZIP domain must undergo a large conformational rearrangement that is controlled by a ‘redox switch’ centered on an inter-molecular disulfide bond. Solution studies confirm that FosB/JunD cannot undergo structural transition and bind DNA when the redox-switch is in the ‘OFF’ state, and show that the mid-point redox potential of the redox switch affords it sensitivity to cellular redox homeostasis. The molecular and structural studies presented here thus reveal the mechanism underlying redox-regulation of AP-1 Fos/Jun transcription factors and provide structural insight for therapeutic interventions targeting AP-1 proteins.},
doi = {10.1093/nar/gkx795},
journal = {Nucleic Acids Research},
number = 19,
volume = 45,
place = {United States},
year = {Thu Sep 07 00:00:00 EDT 2017},
month = {Thu Sep 07 00:00:00 EDT 2017}
}
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Works referenced in this record:
Redox Control of Protein–DNA Interactions: From Molecular Mechanisms to Significance in Signal Transduction, Gene Expression, and DNA Replication
journal, November 2010
- Shlomai, Joseph
- Antioxidants & Redox Signaling, Vol. 13, Issue 9
Redox regulation of fos and jun DNA-binding activity in vitro
journal, September 1990
- Abate, C.; Patel, L.; Rauscher, F.
- Science, Vol. 249, Issue 4973
AP-1 as a regulator of cell life and death
journal, May 2002
- Shaulian, Eitan; Karin, Michael
- Nature Cell Biology, Vol. 4, Issue 5
Crystal structure of the heterodimeric bZIP transcription factor c-Fos–c-Jun bound to DNA
journal, January 1995
- Glover, J. N. Mark; Harrison, Stephen C.
- Nature, Vol. 373, Issue 6511
Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains
journal, March 1989
- Gentz, R.; Rauscher, F.; Abate, C.
- Science, Vol. 243, Issue 4899
Altered protein conformation on DNA binding by Fos and Jun
journal, October 1990
- Patel, Lekha; Abate, Cory; Curran, Tom
- Nature, Vol. 347, Issue 6293
Coupling of folding and DNA-binding in the bZIP domains of Jun–Fos heterodimeric transcription factor
journal, May 2008
- Seldeen, Kenneth L.; McDonald, Caleb B.; Deegan, Brian J.
- Archives of Biochemistry and Biophysics, Vol. 473, Issue 1
N-Terminal Segments Modulate the α-Helical Propensities of the Intrinsically Disordered Basic Regions of bZIP Proteins
journal, February 2012
- Das, Rahul K.; Crick, Scott L.; Pappu, Rohit V.
- Journal of Molecular Biology, Vol. 416, Issue 2
Transcriptional mechanisms of addiction: role of ΔFosB
journal, July 2008
- Nestler, Eric J.
- Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 363, Issue 1507
[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997
- Otwinowski, Zbyszek; Minor, Wladek
- Macromolecular Crystallography Part A, 307-326
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
PHENIX : building new software for automated crystallographic structure determination
journal, October 2002
- Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
Optimal description of a protein structure in terms of multiple groups undergoing TLS motion
journal, March 2006
- Painter, Jay; Merritt, Ethan A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 4
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Presenting your structures: the CCP 4 mg molecular-graphics software
journal, March 2011
- McNicholas, S.; Potterton, E.; Wilson, K. S.
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
COBALT: constraint-based alignment tool for multiple protein sequences
journal, March 2007
- Papadopoulos, J. S.; Agarwala, R.
- Bioinformatics, Vol. 23, Issue 9
Redox Potential and Peroxide Reactivity of Human Peroxiredoxin 3
journal, July 2009
- Cox, Andrew G.; Peskin, Alexander V.; Paton, Louise N.
- Biochemistry, Vol. 48, Issue 27
Parameters of helix-coil transition theory for alanine-based peptides of varying chain lengths in water
journal, November 1991
- Scholtz, J. Martin; Qian, Hong; York, Eunice J.
- Biopolymers, Vol. 31, Issue 13
The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin
journal, March 2005
- Veldkamp, C. T.
- Protein Science, Vol. 14, Issue 4
Ligand binding assays at equilibrium: validation and interpretation: Equilibrium binding assays
journal, February 2010
- Hulme, Edward C.; Trevethick, Mike A.
- British Journal of Pharmacology, Vol. 161, Issue 6
On the analysis of protein self-association by sedimentation velocity analytical ultracentrifugation
journal, September 2003
- Schuck, Peter
- Analytical Biochemistry, Vol. 320, Issue 1
Macromolecular Size-and-Shape Distributions by Sedimentation Velocity Analytical Ultracentrifugation
journal, June 2006
- Brown, Patrick H.; Schuck, Peter
- Biophysical Journal, Vol. 90, Issue 12
Structural basis of DNA bending and oriented heterodimer binding by the basic leucine zipper domains of Fos and Jun
journal, May 1997
- Leonard, D. A.; Rajaram, N.; Kerppola, T. K.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 10
Two cysteine residues in the DNA-binding domain of CREB control binding to CRE and CREB-mediated gene expression
journal, November 2001
- Goren, Itamar; Tavor, Einat; Goldblum, Amiram
- Journal of Molecular Biology, Vol. 313, Issue 4
Folding transition in the DMA-binding domain of GCN4 on specific binding to DNA
journal, October 1990
- Weiss, Michael A.; Ellenberger, Thomas; Wobbe, C. Richard
- Nature, Vol. 347, Issue 6293
X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil
journal, October 1991
- O'Shea, E.; Klemm, J.; Kim, P.
- Science, Vol. 254, Issue 5031
Oxidized redox state of glutathione in the endoplasmic reticulum
journal, September 1992
- Hwang, C.; Sinskey, A.; Lodish, H.
- Science, Vol. 257, Issue 5076
Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity.
journal, February 1992
- Xanthoudakis, S.; Curran, T.
- The EMBO Journal, Vol. 11, Issue 2
Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme.
journal, September 1992
- Xanthoudakis, S.; Miao, G.; Wang, F.
- The EMBO Journal, Vol. 11, Issue 9
Coactivator MBF1 preserves the redox-dependent AP-1 activity during oxidative stress in Drosophila
journal, August 2004
- Jindra, Marek; Gaziova, Ivana; Uhlirova, Mirka
- The EMBO Journal, Vol. 23, Issue 17
Differential roles for Fos and Jun in DNA-binding: redoxdependent and independent functions
journal, January 1993
- Ng, Lily; Forrest, Douglas; Curran, Tom
- Nucleic Acids Research, Vol. 21, Issue 25
JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress
journal, September 2004
- Gerald, Damien; Berra, Edurne; Frapart, Yves M.
- Cell, Vol. 118, Issue 6
Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1): Miniperspective
journal, May 2014
- Ye, Na; Ding, Ye; Wild, Christopher
- Journal of Medicinal Chemistry, Vol. 57, Issue 16
Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1
journal, June 2008
- Aikawa, Yukihiko; Morimoto, Kimiko; Yamamoto, Tetsuya
- Nature Biotechnology, Vol. 26, Issue 7
Small Molecule Screening Identifies Regulators of the Transcription Factor ΔFosB
journal, April 2012
- Wang, Yun; Cesena, Teresa I.; Ohnishi, Yoko
- ACS Chemical Neuroscience, Vol. 3, Issue 7
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity.
journal, February 1992
- Xanthoudakis, S.; Curran, T.
- The EMBO Journal, Vol. 11, Issue 2
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
Two cysteine residues in the DNA-binding domain of CREB control binding to CRE and CREB-mediated gene expression
journal, November 2001
- Goren, Itamar; Tavor, Einat; Goldblum, Amiram
- Journal of Molecular Biology, Vol. 313, Issue 4
Coupling of folding and DNA-binding in the bZIP domains of Jun–Fos heterodimeric transcription factor
journal, May 2008
- Seldeen, Kenneth L.; McDonald, Caleb B.; Deegan, Brian J.
- Archives of Biochemistry and Biophysics, Vol. 473, Issue 1
Size-Distribution Analysis of Macromolecules by Sedimentation Velocity Ultracentrifugation and Lamm Equation Modeling
journal, March 2000
- Schuck, Peter
- Biophysical Journal, Vol. 78, Issue 3
Redox Potential and Peroxide Reactivity of Human Peroxiredoxin 3
journal, July 2009
- Cox, Andrew G.; Peskin, Alexander V.; Paton, Louise N.
- Biochemistry, Vol. 48, Issue 27
Small Molecule Screening Identifies Regulators of the Transcription Factor ΔFosB
journal, April 2012
- Wang, Yun; Cesena, Teresa I.; Ohnishi, Yoko
- ACS Chemical Neuroscience, Vol. 3, Issue 7
Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1
journal, June 2008
- Aikawa, Yukihiko; Morimoto, Kimiko; Yamamoto, Tetsuya
- Nature Biotechnology, Vol. 26, Issue 7
Coactivator MBF1 preserves the redox-dependent AP-1 activity during oxidative stress in Drosophila
journal, August 2004
- Jindra, Marek; Gaziova, Ivana; Uhlirova, Mirka
- The EMBO Journal, Vol. 23, Issue 17
Structural basis of DNA bending and oriented heterodimer binding by the basic leucine zipper domains of Fos and Jun
journal, May 1997
- Leonard, D. A.; Rajaram, N.; Kerppola, T. K.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 10
Redox Control of Protein–DNA Interactions: From Molecular Mechanisms to Significance in Signal Transduction, Gene Expression, and DNA Replication
journal, November 2010
- Shlomai, Joseph
- Antioxidants & Redox Signaling, Vol. 13, Issue 9
COBALT: constraint-based alignment tool for multiple protein sequences
journal, March 2007
- Papadopoulos, J. S.; Agarwala, R.
- Bioinformatics, Vol. 23, Issue 9
Differential roles for Fos and Jun in DNA-binding: redoxdependent and independent functions
journal, January 1993
- Ng, Lily; Forrest, Douglas; Curran, Tom
- Nucleic Acids Research, Vol. 21, Issue 25
The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin
journal, March 2005
- Veldkamp, C. T.
- Protein Science, Vol. 14, Issue 4
Oxidized redox state of glutathione in the endoplasmic reticulum
journal, September 1992
- Hwang, C.; Sinskey, A.; Lodish, H.
- Science, Vol. 257, Issue 5076
X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil
journal, October 1991
- O'Shea, E.; Klemm, J.; Kim, P.
- Science, Vol. 254, Issue 5031
Redox regulation of fos and jun DNA-binding activity in vitro
journal, September 1990
- Abate, C.; Patel, L.; Rauscher, F.
- Science, Vol. 249, Issue 4973
Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains
journal, March 1989
- Gentz, R.; Rauscher, F.; Abate, C.
- Science, Vol. 243, Issue 4899
Redox-Dependent Transcriptional Regulation
journal, November 2005
- Liu, Hongjun; Colavitti, Renata; Rovira, Ilsa I.
- Circulation Research, Vol. 97, Issue 10
Macromolecular Size-and-Shape Distributions by Sedimentation Velocity Analytical Ultracentrifugation
journal, June 2006
- Brown, Patrick H.; Schuck, Peter
- Biophysical Journal, Vol. 90, Issue 12
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
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journal, February 2020
- Castelli, Meghan A.; Whiteley, Sarah L.; Georges, Arthur
- Biological Reviews, Vol. 95, Issue 3
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- Yin, Zhou
- Taylor & Francis
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journal, April 2020
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- Journal of Biomolecular Structure and Dynamics, Vol. 39, Issue 7