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7jfm

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Crystal 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7jfm"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7jfm is ON HOLD
+==Crystal structure of mouse phosphorylated IRF-3 bound to CBP==
+<StructureSection load='7jfm' size='340' side='right'caption='[[7jfm]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7jfm]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JFM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JFM FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.23&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7jfm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jfm OCA], [https://pdbe.org/7jfm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jfm RCSB], [https://www.ebi.ac.uk/pdbsum/7jfm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jfm ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/IRF3_MOUSE 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).<ref>PMID:15800576</ref> <ref>PMID:16846591</ref> <ref>PMID:16979567</ref> <ref>PMID:20049431</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Li, P., Jing, T., Zhao, B.
+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<ref>PMID:32826280</ref>
-Description: Crystal structure of mouse phosphorylated IRF-3 bound to CBP
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhao, B]]
+<div class="pdbe-citations 7jfm" style="background-color:#fffaf0;"></div>
-[[Category: Jing, T]]
-[[Category: Li, P]]
+==See Also==
+*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]]
+*[[Interferon regulatory factor|Interferon regulatory factor]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Jing T]]
+[[Category: Li P]]
+[[Category: Zhao B]]

7jfm

From Proteopedia

Current revision

Crystal structure of mouse phosphorylated IRF-3 bound to CBP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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