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X-ray crystal structure of IRF-3 and its functional implications

Nature Structural & Molecular Biology volume 10, pages 922–927 (2003)Cite this article

Abstract

Transcription factor IRF-3 is post-translationally activated by Toll-like receptor (TLR) signaling and has critical roles in the regulation of innate immunity. Here we present the X-ray crystal structure of the C-terminal regulatory domain of IRF-3(175–427) (IRF-3 175C) at a resolution of 2.3 Å. IRF-3 175C is structurally similar to the Mad homology domain 2 of the Smad family. Structural and functional analyses reveal phosphorylation-induced IRF-3 dimerization, which generates an extensive acidic pocket responsible for binding with p300/CBP. Although TLR and Smad signaling are evolutionarily independent, our results suggest that IRF-3 originates from Smad and acquires its function downstream of TLR.

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Figure 1: Domain structure of IRF-3 and sequence alignment and characterization of IRF-3 175C.
Figure 2: Overall structure of IRF-3 and its structural similarity to Smad2.
Figure 3: The dimer interface of IRF-3.
Figure 4: Phosphorylation of the 2S site and the dimerization of IRF-3 by TBK-1.
Figure 5: Acidic surface of IRF-3.

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Acknowledgements

This work was supported by grant-in-aids for CREST of Japan Science and Technology, Scientific Research on Priority Areas and National Project on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science and Technology, Japan to F.I.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, 060-0812, Japan

    Kiyohiro Takahasi, Masataka Horiuchi & Fuyuhiko Inagaki

  2. CREST/JST, Kawaguchi, Japan

    Nobuo N Suzuki, Masataka Horiuchi & Fuyuhiko Inagaki

  3. Department of Tumor Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8618, Japan

    Mitsuaki Mori, Wakako Suhara, Yasutaka Okabe, Yukiko Fukuhara & Takashi Fujita

  4. Department of Molecular Physiology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8618, Japan

    Hiroaki Terasawa

  5. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Shizuo Akira

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  1. Kiyohiro Takahasi
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Correspondence to Fuyuhiko Inagaki.

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Takahasi, K., Suzuki, N., Horiuchi, M. et al. X-ray crystal structure of IRF-3 and its functional implications. Nat Struct Mol Biol 10, 922–927 (2003). https://doi.org/10.1038/nsb1001

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