| Structural highlights
Function
IL33_HUMAN Cytokine that binds to and signals through IL1RL1/ST2 and its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Induces T-helper type 2-associated cytokines. Acts as a chemoattractant tor Th2 cells, and may function as an "alarmin", that amplifies immune responses during tissue injury.[1] [2] [3] [4] [5] [6] [7] In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or proinflammatory activation.[8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 A. Coupled with structure-based mutagenesis and binding assay, the structural results define the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from small-angle X-ray-scattering analysis resembles IL-1beta-IL-1RII-IL-1RAcP and IL-1beta-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand-receptor assembly and activation in the IL-1 family.
Structural insights into the interaction of IL-33 with its receptors.,Liu X, Hammel M, He Y, Tainer JA, Jeng US, Zhang L, Wang S, Wang X Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14918-23. doi:, 10.1073/pnas.1308651110. Epub 2013 Aug 26. PMID:23980170[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005 Nov;23(5):479-90. PMID:16286016 doi:S1074-7613(05)00311-0
- ↑ Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol. 2007 Oct;37(10):2779-86. PMID:17853410 doi:10.1002/eji.200737547
- ↑ Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G, Girard JP. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):282-7. Epub 2006 Dec 21. PMID:17185418 doi:10.1073/pnas.0606854104
- ↑ Kuchler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR, De Angelis PM, Scott H, Haraldsen G. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol. 2008 Oct;173(4):1229-42. doi: 10.2353/ajpath.2008.080014. Epub 2008 , Sep 11. PMID:18787100 doi:10.2353/ajpath.2008.080014
- ↑ Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One. 2008 Oct 6;3(10):e3331. doi: 10.1371/journal.pone.0003331. PMID:18836528 doi:10.1371/journal.pone.0003331
- ↑ Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU. The dual function cytokine IL-33 interacts with the transcription factor NF-kappaB to dampen NF-kappaB-stimulated gene transcription. J Immunol. 2011 Aug 15;187(4):1609-16. doi: 10.4049/jimmunol.1003080. Epub 2011, Jul 6. PMID:21734074 doi:10.4049/jimmunol.1003080
- ↑ Kakkar R, Hei H, Dobner S, Lee RT. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem. 2012 Feb 24;287(9):6941-8. doi: 10.1074/jbc.M111.298703. Epub 2012, Jan 3. PMID:22215666 doi:10.1074/jbc.M111.298703
- ↑ Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005 Nov;23(5):479-90. PMID:16286016 doi:S1074-7613(05)00311-0
- ↑ Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol. 2007 Oct;37(10):2779-86. PMID:17853410 doi:10.1002/eji.200737547
- ↑ Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G, Girard JP. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):282-7. Epub 2006 Dec 21. PMID:17185418 doi:10.1073/pnas.0606854104
- ↑ Kuchler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR, De Angelis PM, Scott H, Haraldsen G. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol. 2008 Oct;173(4):1229-42. doi: 10.2353/ajpath.2008.080014. Epub 2008 , Sep 11. PMID:18787100 doi:10.2353/ajpath.2008.080014
- ↑ Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One. 2008 Oct 6;3(10):e3331. doi: 10.1371/journal.pone.0003331. PMID:18836528 doi:10.1371/journal.pone.0003331
- ↑ Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU. The dual function cytokine IL-33 interacts with the transcription factor NF-kappaB to dampen NF-kappaB-stimulated gene transcription. J Immunol. 2011 Aug 15;187(4):1609-16. doi: 10.4049/jimmunol.1003080. Epub 2011, Jul 6. PMID:21734074 doi:10.4049/jimmunol.1003080
- ↑ Kakkar R, Hei H, Dobner S, Lee RT. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem. 2012 Feb 24;287(9):6941-8. doi: 10.1074/jbc.M111.298703. Epub 2012, Jan 3. PMID:22215666 doi:10.1074/jbc.M111.298703
- ↑ Liu X, Hammel M, He Y, Tainer JA, Jeng US, Zhang L, Wang S, Wang X. Structural insights into the interaction of IL-33 with its receptors. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14918-23. doi:, 10.1073/pnas.1308651110. Epub 2013 Aug 26. PMID:23980170 doi:10.1073/pnas.1308651110
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