Nucleic Acids Research Advance Access originally published online on May 5, 2007
Nucleic Acids Research 2007 35(11):3525-3534; doi:10.1093/nar/gkm142
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Nucleic Acids Research, 2007, Vol. 35, No. 11 3525-3534
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Mechanisms of activation of interferon regulator factor 3: the role of C-terminal domain phosphorylation in IRF-3 dimerization and DNA binding
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
*To whom correspondence should be addressed. Tel: +1-410-516-4706; Fax: +1-410-261-1054; Email: dragan{at}jhu.edu
Received December 13, 2006. Revised February 21, 2007. Accepted February 21, 2007.
The interferon regulatory transcription factor (IRF-3) is activated by phosphorylation of Ser/Thr residues clustered in its C-terminal domain. Phosphorylation of these residues, which increases the negative charge of IRF-3, results in its dimerization and association with DNA, despite the increase in repulsive electrostatic interactions. To investigate this surprising effect, the dimerization of IRF-3 and two phosphomimetic mutants, 2D (S396D, S398D) and 5D (S396D, S398D, S402D, T404D and S405D), and their binding to single-site PRDI and double-site PRDIII–PRDI DNA sequences from the IFN-ß enhancer have been studied. It was found that: (a) the mutations in the C-terminal domain do not affect the state of the DNA-binding N-terminal domain or its ability to bind target DNA; (b) in the 5D-mutant, the local increase of negative charge in the C-terminal domain induces restructuring, resulting in the formation of a stable dimer; (c) dimerization of IRF-3 is the basis of its strong binding to PRDIII–PRDI sites since binding of 5D to the single PRDI site is similar to that of inactivated IRF-3. Analysis of the binding characteristics leads to the conclusion that binding of dimeric IRF-3 to the DNA with two tandem-binding sites, which are twisted by 
100° relative to each other, requires considerable work to untwist and/or bend the DNA.
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