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Title: 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:
; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1409105
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nucleic Acids Research; Journal Volume: 45; Journal Issue: 19
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. doi:10.1093/nar/gkx795.
Yin, Zhou, Machius, Mischa, Nestler, Eric J., and Rudenko, Gabby. 2017. "Activator Protein-1: redox switch controlling structure and DNA-binding". United States. doi:10.1093/nar/gkx795.
@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 = 2017,
month = 9
}
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