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Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5.

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.

Pubmed ID: 18836453

Authors

  • Chen W
  • Lam SS
  • Srinath H
  • Jiang Z
  • Correia JJ
  • Schiffer CA
  • Fitzgerald KA
  • Lin K
  • Royer WE

Journal

Nature structural & molecular biology

Publication Data

November 5, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI056080
  • Agency: NIAID NIH HHS, Id: AI067497
  • Agency: NIBIB NIH HHS, Id: P30 EB009998
  • Agency: NIAID NIH HHS, Id: R01 AI056080-04
  • Agency: NIAID NIH HHS, Id: R01 AI067497
  • Agency: NIAID NIH HHS, Id: R01 AI067497-03
  • Agency: NIAID NIH HHS, Id: R01 AI067497-05

Mesh Terms

  • 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