Structures of apo IRF-3 and IRF-7 DNA binding domains: effect of loop L1 on DNA binding

Interferon regulatory factors IRF-3 and IRF-7 are transcription factors essential in the activation of interferon-β (IFN-β) gene in response to viral infections. Although, both proteins recognize the same consensus IRF binding site AANNGAAA, they have distinct DNA binding preferences for sites in vi...

Full description

Saved in:
Bibliographic Details
Published in:Nucleic acids research 2011-09, Vol.39 (16), p.7300-7307
Main Authors: De Ioannes, Pablo, Escalante, Carlos R, Aggarwal, Aneel K
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ALANINES
Amino Acid Sequence
Animals
BASIC BIOLOGICAL SCIENCES
CONFORMATIONAL CHANGES
Crystallography, X-Ray
DNA
DNA - chemistry
FLEXIBILITY
GENES
HISTIDINE
Humans
IN VIVO
INTERFERON
Interferon Regulatory Factor-3 - chemistry
Interferon Regulatory Factor-3 - genetics
Interferon Regulatory Factor-7 - chemistry
Interferon Regulatory Factor-7 - genetics
Mice
Models, Molecular
Molecular Sequence Data
Mutation
PROMOTERS
Protein Binding
Protein Structure, Tertiary
PROTEINS
RESIDUES
STABILITY
Structural Biology
TARGETS
TRANSCRIPTION FACTORS
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Interferon regulatory factors IRF-3 and IRF-7 are transcription factors essential in the activation of interferon-β (IFN-β) gene in response to viral infections. Although, both proteins recognize the same consensus IRF binding site AANNGAAA, they have distinct DNA binding preferences for sites in vivo. The X-ray structures of IRF-3 and IRF-7 DNA binding domains (DBDs) bound to IFN-β promoter elements revealed flexibility in the loops (L1-L3) and the residues that make contacts with the target sequence. To characterize the conformational changes that occur on DNA binding and how they differ between IRF family members, we have solved the X-ray structures of IRF-3 and IRF-7 DBDs in the absence of DNA. We found that loop L1, carrying the conserved histidine that interacts with the DNA minor groove, is disordered in apo IRF-3 but is ordered in apo IRF-7. This is reflected in differences in DNA binding affinities when the conserved histidine in loop L1 is mutated to alanine in the two proteins. The stability of loop L1 in IRF-7 derives from a unique combination of hydrophobic residues that pack against the protein core. Together, our data show that differences in flexibility of loop L1 are an important determinant of differential IRF-DNA binding.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkr325