7uwl

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Structure of the IL-25-IL-17RB-IL-17RA ternary complex

Structural highlights

7uwl is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.7Å
Ligands:NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IL25_HUMAN Cytokine produced by various cells such as eosinophils, T-helper type 2 (Th2) cells or epithelial cells that plays a role in internal safety of adaptive immune responses by regulating cytokine production (PubMed:15860795, PubMed:25821217). Promotes and augments T-helper type 2 responses locally or systemically (PubMed:25821217). Exerts its activity via its receptor composed of IL17RA and IL17RB for signal transduction (By similarity). In turn, stimulates the JAK2-STAT5A pathway and promotes the secretion of type-2 associated cytokines including IL4, IL9 and IL13 (PubMed:25821217). Induces also the release of IL8, and IL6 from eosinophils through the combined activation of MAPK and NF-kappa-B pathways (PubMed:15860795). Inhibits the differentiation of T-helper (Th17) cells via the production of IL4, IL5 and IL13 (PubMed:11754819).[UniProtKB:Q8VHH8][1] [2] [3]

Publication Abstract from PubMed

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases(1). The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses(2). Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25-IL-17RB homodimer is flanked by two 'wing-like' IL-17RA co-receptors through a 'tip-to-tip' geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB-IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A-IL-17RA and IL-17A-IL-17RA-IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.

Organizing structural principles of the IL-17 ligand-receptor axis.,Wilson SC, Caveney NA, Yen M, Pollmann C, Xiang X, Jude KM, Hafer M, Tsutsumi N, Piehler J, Garcia KC Nature. 2022 Sep;609(7927):622-629. doi: 10.1038/s41586-022-05116-y. Epub 2022 , Jul 21. PMID:35863378[4]

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

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See Also

References

  1. ↑ Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001 Dec;15(6):985-95. PMID:11754819 doi:10.1016/s1074-7613(01)00243-6
  2. ↑ Wong CK, Cheung PF, Ip WK, Lam CW. Interleukin-25-induced chemokines and interleukin-6 release from eosinophils is mediated by p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB. Am J Respir Cell Mol Biol. 2005 Aug;33(2):186-94. PMID:15860795 doi:10.1165/rcmb.2005-0034OC
  3. ↑ Wu L, Zepp JA, Qian W, Martin BN, Ouyang W, Yin W, Bunting KD, Aronica M, Erzurum S, Li X. A novel IL-25 signaling pathway through STAT5. J Immunol. 2015 May 1;194(9):4528-34. PMID:25821217 doi:10.4049/jimmunol.1402760
  4. ↑ Wilson SC, Caveney NA, Yen M, Pollmann C, Xiang X, Jude KM, Hafer M, Tsutsumi N, Piehler J, Garcia KC. Organizing structural principles of the IL-17 ligand-receptor axis. Nature. 2022 Jul 21. pii: 10.1038/s41586-022-05116-y. doi:, 10.1038/s41586-022-05116-y. PMID:35863378 doi:http://dx.doi.org/10.1038/s41586-022-05116-y

Contents


PDB ID 7uwl

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