5vi4 | pdb_00005vi4
IL-33/ST2/IL-1RAcP ternary complex structure
Structural highlights
Function[IL33_MOUSE] Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as a chemoattractant for Th2 cells, and may function as an "alarmin", that amplifies immune responses during tissue injury. 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. [IL1AP_MOUSE] Coreceptor for IL1RL2 in the IL-36 signaling system. Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Secreted forms (isoforms 2 and 3) associate with secreted ligand-bound IL1R2 and increase the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors.[UniProtKB:Q9NPH3][1] [ILRL1_MOUSE] Receptor for interleukin-33 (IL-33); signaling requires association of the coreceptor IL1RAP (PubMed:18450470, PubMed:17675517). Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8 (By similarity). Possibly involved in helper T-cell function.[UniProtKB:Q01638][2] [3] Isoform B: Inhibits IL-33 signaling.[4] Publication Abstract from PubMedWithin the interleukin 1 (IL-1) cytokine family, IL-1 receptor accessory protein (IL-1RAcP) is the co-receptor for eight receptor-cytokine pairs, including those involving cytokines IL-1beta and IL-33. Unlike IL-1beta, IL-33 does not have a signaling complex that includes both its cognate receptor, ST2, and the shared co-receptor IL-1RAcP, which we now present here. Although the IL-1beta and IL-33 complexes shared structural features and engaged identical molecular surfaces of IL-1RAcP, these cytokines had starkly different strategies for co-receptor engagement and signal activation. Our data suggest that IL-1beta binds to IL-1RI to properly present the cytokine to IL-1RAcP, whereas IL-33 binds to ST2 in order to conformationally constrain the cognate receptor in an IL-1RAcP-receptive state. These findings indicate that members of the IL-1 family of cytokines use distinct molecular mechanisms to signal through their shared co-receptor, and they provide the foundation from which to design new therapies to target IL-33 signaling. IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor.,Gunther S, Deredge D, Bowers AL, Luchini A, Bonsor DA, Beadenkopf R, Liotta L, Wintrode PL, Sundberg EJ Immunity. 2017 Sep 19;47(3):510-523.e4. doi: 10.1016/j.immuni.2017.08.004. PMID:28930661[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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