Structure of IL-33 and Its Interaction with the ST2 and IL-1RAcP Receptors—Insight into Heterotrimeric IL-1 Signaling Complexes

Lingel, Andreas; Weiß, Thomas; Niebuhr, Marc; Pan, Borlan; Appleton, B.A.; Wiesmann, Christian; Bazán, J. Fernando; Fairbrother, Wayne J.

doi:10.1016/j.str.2009.08.009

Cited by 180 publications

(165 citation statements)

References 56 publications

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“…s.d. of 1.2 Å for 123 matched Cα atoms (30). Twelve β-strands forming the β-trefoil fold are conserved in both structures, whereas conformational variations reside in the loops connecting the strands, especially in loops β2-β3, β3-β4, β4-β5, β10-β11, and β11-β12 involved in receptor interaction (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous efforts to identify "hot spot" residues of IL-33 for ST2 interaction were based on NMR chemical-shift perturbation data and subsequent mutagenesis and affinity measurements (30). Twenty-eight IL-33 mutants were examined, and only one mutant (E144K) had a pronounced effect on the interaction between IL-33 and ST2 by decreasing the affinity sevenfold from 0.45 to 3.15 nM (30).…”

Section: Resultsmentioning

confidence: 99%

“…Twenty-eight IL-33 mutants were examined, and only one mutant (E144K) had a pronounced effect on the interaction between IL-33 and ST2 by decreasing the affinity sevenfold from 0.45 to 3.15 nM (30). We measured the ST2-binding affinities of IL-33 mutants identified by structural analysis of the IL-33/ST2 interface with surface plasmon resonance (SPR) method (Table S2).…”

Section: Resultsmentioning

confidence: 99%

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Structural insights into the interaction of IL-33 with its receptors

Liu

Hammel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

170

193

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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 Å. 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 smallangle X-ray-scattering analysis resembles IL-1β-IL-1RII-IL-1RAcP and IL-1β-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.protein-protein interaction | X-ray crystallography | SAXS | cytokine signaling I nterleukin (IL)-33 has important roles in initiating a type 2 immune response during infectious, inflammatory, and allergic diseases (1-5). It was initially identified as a nuclear factor in endothelial cells and named NF-HEV (nuclear factor from high endothelial venules) (6, 7). In 2005, it was rediscovered as a new member of the IL-1 family and an extracellular ligand for the orphan IL-1 receptor family member ST2 (8). As an extracellular cytokine, IL-33 is involved in the polarization of Th2 cells and activation of mast cells, basophils, eosinophils, and natural killer cells (1-3). Recent studies also discovered that the type 2 innate lymphoid cells (ILC2s) are major target cells of IL-33 (9, 10). ILC2s express a high level of ST2 and secrete large amounts of Th2 cytokines, most notably IL-5 and IL-13, when stimulated with . Activation of ILC2s is essential in the initiation of the type 2 immune response against helminth infection and during allergic diseases such as asthma (9, 10).IL-33 does not have a signal peptide and is synthesized with an N-terminal propeptide upstream of the IL-1-like cytokine domain. It is preferentially and constitutively expressed in the nuclei of structural and lining cells, particularly in epithelial and endothelial cells (14,15). Tissue damage caused by pathogen invasio...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Structural insights into the interaction of IL-33 with its receptors

Liu

Hammel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

170

193

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“…For instance, IL-33 has been shown to be heterochromatin associated, functioning as a transcriptional repressor in living cells (2). In contrast, IL-33 is known to signal via a transmembrane receptor complex of ST2 and Interelukin-1 receptor accessory protein, activating downstream tyrosine kinases and modulating NF-B activity (3,4). As IL-33 is cleaved at its receptor binding site by caspase 3 in the context of cellular apoptosis,(5) it has been suggested that IL-33 is released from the nuclear space only during necrosis, whereby it is free to bind its cell surface receptor and affect paracrine inflammatory signaling.…”

mentioning

confidence: 99%

Interleukin 33 as a mechanically responsive cytokine secreted by living cells

Kakkar¹,

Hei²,

Dobner³

et al. 2014

Thorac cardiovasc Surg

108

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Background: Conflicting data describe Interleukin 33 as a nuclear factor and ligand for a transmembrane receptor complex. Results: IL-33 displays multi-compartmental geography, inter-organelle flux and extracellular release from mechanically stressed cells. Conclusion: IL-33 manifests dynamic subcellular mobility and secretion from living cells upon biomechanical strain. Significance: IL-33 belongs to a group of factors displaying dual inflammatory and mechano-responsive properties.

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“…It was identified as a member of the IL-1 cytokine family when ST2/T1, hitherto an orphan receptor in the IL-1R family, was found to be the receptor for IL-33 (3). IL-33 functions as a classical cytokine by binding to its specific plasma membrane receptor (3), now designated IL-33Ra-chain (4), and by recruiting the IL-1R accessory protein into a trimeric complex (5)(6)(7)(8), inducing signaling pathways similar to those of IL-1 (5-7). IL-33 acts on many different cells types, including Th2 lymphocytes and mast cells (reviewed in Ref.…”

mentioning

confidence: 99%

The Dual Function Cytokine IL-33 Interacts with the Transcription Factor NF-κB To Dampen NF-κB–Stimulated Gene Transcription

Ali

Mohs

Thomas

et al. 2011

The Journal of Immunology

299

232

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Full-length IL-33 is a member of the IL-1 family of cytokines, which can act in an autocrine or paracrine manner by binding to the IL-33R on several different target cell types. In addition, IL-33 can act in an intracrine fashion by translocating to the nucleus, where it binds to the chromatin and modulates gene expression. In this article, we report that full-length IL-33, but not mature IL-33, interacts with the transcription factor NF-κB. This interaction occurs between the N-terminal part of IL-33 from aa 66–109 and the N-terminal Rel homology domain of NF-κB p65. Coimmunoprecipitation experiments in cells overexpressing IL-33 or endogenously expressing IL-33 revealed rhIL-1β–stimulated association between IL-33 and p65, whereas binding to the p50 subunit was constitutive. The biological consequence of IL-33/NF-κB complex formation was reduction in NF-κB p65 binding to its cognate DNA and impairment of p65-triggered transactivation. Overexpression of IL-33 resulted in a reduction and delay in the rhIL-1β–stimulated expression of endogenous NF-κB target genes such as IκBα, TNF-α, and C-REL. We suggest that nuclear IL-33 sequesters nuclear NF-κB and reduces NF-κB–triggered gene expression to dampen proinflammatory signaling.

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Structure of IL-33 and Its Interaction with the ST2 and IL-1RAcP Receptors—Insight into Heterotrimeric IL-1 Signaling Complexes

Cited by 180 publications

References 56 publications

Structural insights into the interaction of IL-33 with its receptors

Structural insights into the interaction of IL-33 with its receptors

Interleukin 33 as a mechanically responsive cytokine secreted by living cells

The Dual Function Cytokine IL-33 Interacts with the Transcription Factor NF-κB To Dampen NF-κB–Stimulated Gene Transcription

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