4kc3
From Proteopedia
Cytokine/receptor binary complex
Structural highlights
FunctionIL33_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 PubMedInterleukin (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. Loading citation details.. Citations No citations found See AlsoReferences
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