| First Author | Schröder J | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 1 | Pages | 359-70 |
| PubMed ID | 25371211 | Mgi Jnum | J:218399 |
| Mgi Id | MGI:5617423 | Doi | 10.1074/jbc.M114.617597 |
| Citation | Schroder J, et al. (2015) Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor beta1 via site II and induces p19/interleukin 23 receptor interaction via site III. J Biol Chem 290(1):359-70 |
| abstractText | IL-23, composed of the cytokine subunit p19 and the soluble alpha receptor subunit p40, binds to a receptor complex consisting of the IL-23 receptor (IL-23R) and the IL-12 receptor beta1 (IL-12Rbeta1). Complex formation was hypothesized to follow the "site I-II-III" architectural paradigm, with site I of p19 being required for binding to p40, whereas sites II and III of p19 mediate binding to IL-12Rbeta1 and IL-23R, respectively. Here we show that the binding mode of p19 to p40 and of p19 to IL-23R follow the canonical site I and III paradigm but that interaction of IL-23 to IL-12Rbeta1 is independent of site II in p19. Instead, binding of IL-23 to the cytokine binding module of IL-12Rbeta1 is mediated by domains 1 and 2 of p40 via corresponding site II amino acids of IL-12Rbeta1. Moreover, domains 2 and 3 of p40 were sufficient for complex formation with p19 and to induce binding of p19 to IL-23R. The Fc-tagged fusion protein of p40_D2D3/p19 did, however, not act as a competitive IL-23 antagonist but, at higher concentrations, induced proliferation via IL-23R but independent of IL-12Rbeta1. On the basis of our experimental validation, we propose a non-canonical topology of the IL-23.IL-23R.IL-12Rbeta1 complex. Furthermore, our data help to explain why p40 is an antagonist of IL-23 and IL-12 signaling and show that site II of p19 is dispensable for IL-23 signaling. |
