Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5
Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Infectious Disease and Immunology
*Crystallography, X-Ray; Dimerization; Humans; Interferon Regulatory Factors; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphorylation; *Protein Structure, Quaternary; *Protein Structure, Tertiary; Serine; Thermodynamics
Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health
Interferon regulatory factors (IRFs) are essential in the innate immune response and other physiological processes. Activation of these proteins in the cytoplasm is triggered by phosphorylation of serine and threonine residues in a C-terminal autoinhibitory region, which stimulates dimerization, transport into the nucleus, assembly with the coactivator CBP/p300 and initiation of transcription. The crystal structure of the transactivation domain of pseudophosphorylated human IRF5 strikingly reveals a dimer in which the bulk of intersubunit interactions involve a highly extended C-terminal region. The corresponding region has previously been shown to block CBP/p300 binding to unphosphorylated IRF3. Mutation of key interface residues supports the observed dimer as the physiologically activated state of IRF5 and IRF3. Thus, phosphorylation is likely to activate IRF5 and other family members by triggering conformational rearrangements that switch the C-terminal segment from an autoinihibitory to a dimerization role.
DOI of Published Version
Nat Struct Mol Biol. 2008 Nov;15(11):1213-20. Epub 2008 Oct 5. Link to article on publisher's site
Nature structural and molecular biology
Chen, Weijun; Lam, Suvana S.; Srinath, Hema; Jiang, Zhaozhao; Correia, John J.; Schiffer, Celia A.; Fitzgerald, Katherine A.; Lin, Kai; and Royer, William E., "Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5" (2008). Biochemistry and Molecular Pharmacology Publications and Presentations. 67.