7jfm

Crystal structure of mouse phosphorylated IRF-3 bound to CBPCrystal structure of mouse phosphorylated IRF-3 bound to CBP

Structural highlights

7jfm is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.23Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IRF3_MOUSE Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses (PubMed:15800576). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:15800576). Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction (PubMed:16846591, PubMed:16979567, PubMed:20049431). Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases (PubMed:16846591, PubMed:16979567, PubMed:20049431). This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes (PubMed:16846591, PubMed:16979567, PubMed:20049431). Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages (PubMed:16846591, PubMed:16979567, PubMed:20049431).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The innate immune system is the first line of defense against bacterial and viral infections. The recognition of pathogen-associated molecular patterns by the RIG-I-like receptors, TLRs, and cGAS leads to the induction of IFN-I by activating the transcription factor IRF-3. Although the mechanism of IRF-3 activation has been extensively studied, the structural basis of IRF-3 activation upon phosphorylation is not fully understood. In this study, we determined the crystal structures of phosphorylated human and mouse IRF-3 bound to CREB-binding protein (CBP), which reveal that phosphorylated IRF-3 forms a dimer via pSer(386) (pSer(379) in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer(386) severely impair IRF-3 activation and IFN-beta induction. By contrast, phosphorylation of Ser(396) within the pLxIS motif of human IRF-3 only plays a moderate role in IRF-3 activation. The mouse IRF-3/CBP complex structure reveals that the mechanism of mouse IRF-3 activation is similar but distinct from human IRF-3. These structural and functional studies reveal the detailed mechanism of IRF-3 activation upon phosphorylation.

The Structural Basis of IRF-3 Activation upon Phosphorylation.,Jing T, Zhao B, Xu P, Gao X, Chi L, Han H, Sankaran B, Li P J Immunol. 2020 Aug 21. pii: jimmunol.2000026. doi: 10.4049/jimmunol.2000026. PMID:32826280^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005 Apr 7;434(7034):772-7. Epub 2005 Mar 30. PMID:15800576 doi:http://dx.doi.org/10.1038/nature03464
↑ Solis M, Goubau D, Romieu-Mourez R, Genin P, Civas A, Hiscott J. Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages. Biochem Pharmacol. 2006 Nov 30;72(11):1469-76. PMID:16846591 doi:10.1016/j.bcp.2006.06.002
↑ Honda K, Takaoka A, Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006 Sep;25(3):349-60. PMID:16979567 doi:10.1016/j.immuni.2006.08.009
↑ Savitsky D, Tamura T, Yanai H, Taniguchi T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother. 2010 Apr;59(4):489-510. PMID:20049431 doi:10.1007/s00262-009-0804-6
↑ Jing T, Zhao B, Xu P, Gao X, Chi L, Han H, Sankaran B, Li P. The Structural Basis of IRF-3 Activation upon Phosphorylation. J Immunol. 2020 Oct 1;205(7):1886-1896. PMID:32826280 doi:10.4049/jimmunol.2000026

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OCA

[1] Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005 Apr 7;434(7034):772-7. Epub 2005 Mar 30. PMID:15800576 doi:http://dx.doi.org/10.1038/nature03464

[2] Solis M, Goubau D, Romieu-Mourez R, Genin P, Civas A, Hiscott J. Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages. Biochem Pharmacol. 2006 Nov 30;72(11):1469-76. PMID:16846591 doi:10.1016/j.bcp.2006.06.002

[3] Honda K, Takaoka A, Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006 Sep;25(3):349-60. PMID:16979567 doi:10.1016/j.immuni.2006.08.009

[4] Savitsky D, Tamura T, Yanai H, Taniguchi T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother. 2010 Apr;59(4):489-510. PMID:20049431 doi:10.1007/s00262-009-0804-6

[5] Jing T, Zhao B, Xu P, Gao X, Chi L, Han H, Sankaran B, Li P. The Structural Basis of IRF-3 Activation upon Phosphorylation. J Immunol. 2020 Oct 1;205(7):1886-1896. PMID:32826280 doi:10.4049/jimmunol.2000026

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