1. Academic Validation
  2. Activator Protein-1: redox switch controlling structure and DNA-binding

Activator Protein-1: redox switch controlling structure and DNA-binding

  • Nucleic Acids Res. 2017 Nov 2;45(19):11425-11436. doi: 10.1093/nar/gkx795.
Zhou Yin 1 Mischa Machius 1 Eric J Nestler 2 Gabby Rudenko 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, and the Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 2 Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY 10029, USA.
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.

Figures