IL35 binds IL-12RB2:IL6ST receptor

Stable Identifier
R-HSA-6809140
Type
Reaction [uncertain]
Species
Homo sapiens
Compartment
Synonyms
Interleukin-35 binds Interleukin-35 receptor, Interleukin-35 binds Interleukin-6 receptor beta:Interleukin 12 Receptor beta 2 complex
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Interleukin-35 (IL35) is a heteromeric complex of Interleukin-12 subunit alpha (IL12A) and Interleukin-27 subunit beta (EBI3, IL27B) ) induces hetero and homodimers of Interleukin 6 receptor beta precursor (IL6ST, gp130) and Interleukin 12 receptor beta 2 (IL12RB2). These results suggested that Interleukin 35 is bound to these three receptor subunits providing insight into the partial resistance to Interleukin 35 mediated suppression observed after the deletion of a single chain. Moreover there is the possibility of the assembly of higher structures by Interleukin 35, as has been suggested for Interleukin 6 receptor subunit beta precursor. IL12RB2 and IL6ST represent the most plausible components of Interleukin 35 receptor. However, additional molecules might facilitate cytokine binding or downstream signaling, although this would be unprecedented in the Interleukin 6 receptor and Interleukin 12 receptor families (Collison et al. 2012) Moreover Interleukin 35 (IL35) uses an unique heterodimer of receptor chains Interleukin 12 receptor subunit beta (IL 12RB2) and Interleukin 6 receptor subunit beta (gp130 or IL6ST) for its signal transduction. The composition of Interleukin 35 heterodimeric receptor is not totally elucidated, but Interleukin 35–Interleukin 35 receptor interaction and assembly given the `site 1 2 3' follows an architectural paradigm originally established for Interleukin 6 (IL 6) (Boulanger et al. 2003). Computational analysis suggests 3 potential conformations of Interleukin 35/Interleukin 35 Receptor complex: First, IL6ST binds to site 2 in the Interleukin 6(IL 6), Ciliary neurotrophic factor (CNTF) and LIF (Leukemia inhibitory factor) complexes and thus could do so in the IL 35 IL35R complex, leaving IL12RB2 to bind site 3. Second, the Interleukin 35–Interleukin 35 receptor complex could form symmetric homohexameric assemblies (2:2:2) analogous to the Interleukin 6 receptor complex, thus allowing IL 12RB2 and IL6ST to each bind to site 3 on IL12A. Third, IL6ST and IL12RB2 could both be capable of binding to site 2 and site 3 and therefore exist in an interchanging equilibrium of heterotetrameric complexes (at a ratio of 1:1:1:1, IL6ST to IL12RB2 to Interleukin 27 beta subunit (EBI3). Indeed, studies of the Interleukin 6 ligand receptor complex suggest that it may be able to signal as tetrameric or hexameric assembly. Finally, a previously unknown mode of binding may exist that uses the site 1 2 3 model in a manner not predicted on the basis of the existing structural information for IL 6, LIF and CNTF (Collison et al. 2012). As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as a black box event.

Literature References
PubMed ID Title Journal Year
22306691 The composition and signaling of the IL-35 receptor are unconventional

Collison, LW, Delgoffe, GM, Guy, CS, Vignali, KM, Chaturvedi, V, Fairweather, D, Satoskar, AR, Garcia, KC, Hunter, CA, Drake, CG, Murray, PJ, Vignali, DA

Nat. Immunol. 2012
12829785 Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex

Boulanger, MJ, Chow, DC, Brevnova, EE, Garcia, KC

Science 2003
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