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Review
. 2010 Jun;22(6):883-7.
doi: 10.1016/j.cellsig.2009.12.005. Epub 2009 Dec 30.

Structural insights into interferon regulatory factor activation

Weijun Chen  1 , William E Royer Jr
Affiliations
Review

Structural insights into interferon regulatory factor activation

Weijun Chen et al. Cell Signal. 2010 Jun.

Abstract

The interferon regulatory factors (IRFs) play important roles in development of the immune system and host defense. Recent crystallographic and biochemical studies have provided insights into the mechanism of activation of IRFs by phosphorylation. The activation of a latent closed conformation of IRF in the cytoplasm is triggered by phosphorylation of Ser/Thr residues in a C-terminal region. Phosphorylation stimulates the C-terminal autoinhibitory domain to attain a highly extended conformation triggering dimerization through extensive contacts to a second subunit. Dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes. The advances made in understanding the release of inhibition after IRF dimerization have generated a detailed structural model of how IRFs signaling pathways are activated.

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Figures

Figure 1
Figure 1. Domains structure of IRF-3, IRF-5, and IRF-7
Regions known to participate in protein–protein interactions are indicated by colored boxes. (DBD: DNA-binding domain; IAD: IRF-association domain; NLS: nuclear localization sequence; NES: nuclear export signal; AUD: autoinhibition domain).
Figure 2
Figure 2. The crystal structure of dimeric IRF-5 [47]
A ribbon diagram of the crystallographic IRF5 dimer is shown with one subunit in blue and one in green. Putative phosphorylation sites are shown as yellow balls. The C-terminal region lays across the surface of the second subunit, making extensive contacts particularly involving helix 4, helix 5 and the interhelical region interacting with helix 2′ and loops L1′, L3′ and L5′. (Primes designate the second subunit.)
Figure 3
Figure 3. Ribbon diagrams of the C-terminal transactivation domain of IRF5 and IRF3[47]
Monomers from three crystal structures have been aligned using 138 residues of the IRF-association domain (IAD), highlighted in cyan. The rest of the IAD is in green, the C-terminal autoinhibitory region is in magenta and putative phosphorylation sites are shown as yellow balls. (a) IRF5222–267 S430D has an extended C-terminal region that participates in dimer formation. This leaves most of the CBP binding site, formed by helices 3 and 4, exposed to solvent, except for that the part of the site covered by helix 1. (b) In the autoinhibited IRF3173–427 monomer, the autoinhibitory C-terminal region binds to and masks the CBP binding site31. (c) In the complex of IRF3173–394 with CBP2067–2112, CBP (gold) binds to helices 3 and 4, which are exposed by the removal of residues 395–427, and displaces the N-terminal helix 1.
Figure 4
Figure 4. Model of regulation of IRF-3 activity by phosphorylation, autoinhibition and dimerization
The IAD is colored green. DBD is colored blue. CBP is colored purple. The autoinhibitory structure in the basal state IRF is bound with IAD (red box), however, after phosphorylation, the autoinhibitory structure is moving away from IAD and it is colored green. The phosphorylation target site is shown as yellow spheres. DBD: DNA binding domain IAD: IRF association domain AID: Autoinhibitory domain CBP: CREB binding protein
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