Molecular modeling of the oxidized form of nuclear factor-?B suggests a mechanism for redox regulation of DNA binding and transcriptional activation

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Ethan W Taylor, Senior Research Professor (Creator)
The University of North Carolina at Greensboro (UNCG )
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Abstract: NF-?B is an important transcriptional regulator of numerous cellular genes, as well as viruses such as HIV-1. Oxidative stimuli in the cytosol are associated with nuclear translocation of NF-?B, whereas in the nucleus, reductive activation by thioredoxin is required for NF-?B to bind to DNA and activate target genes. Experimental structures of the reduced form of NF-?B bound to its DNA targets are available, from which we have modeled the oxidized form of NF-?B homodimer by removal of bound DNA, and modification via a hinge movement of a linker between the dimerization and DNA-binding domains of each subunit. These torsional motions enabled the formation of an inter-subunit disulfide bond between the Cys62 residues of each monomer; the resulting structure was refined using molecular dynamics simulation. The final model of oxidized, disulfide-bridged NF-?B is more compact than the open, reduced form. This may facilitate its nuclear translocation through small pores in the nuclear envelope, in response to oxidative stimuli in the cytosol. Furthermore, the inter-subunit disulfide blocks DNA from entering the active site of the oxidized dimer, explaining why subsequent reduction to the thiol form in the nucleus is essential for DNA binding and transcriptional activation to occur.

Additional Information

Journal of Molecular Graphics and Modelling. Volume 26, Issue 5, January 2008, Pages 861-867.
Language: English
Date: 2008
DNA-binding protein, Gene expression, Nuclear factor-?B (NF-?B), Redox regulation, Thioredoxin, Transcription factor

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