TY - JOUR AB - Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immuno-suppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signalling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold2 modelling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signalling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions. AU - Bubeck,D AU - Jin,Y AU - Fyfe,PK AU - Gardner,S AU - Wilmes,S AU - Moraga,I DO - 10.15252/embr.202255450 PY - 2022/// SN - 1469-221X TI - Structural insights into the assembly and activation of the IL-27 signalling complex T2 - EMBO Reports UR - http://dx.doi.org/10.15252/embr.202255450 UR - http://hdl.handle.net/10044/1/98306 VL - 23 ER -