Crystal structure of the IL-15-IL-15Ralpha complex, a cytokine-receptor unit presented in trans
Chirifu M, Hayashi C, Nakamura T, Toma S, Shuto T, Kai H, Yamagata Y, Davis SJ, Ikemizu S. (2007), Nat Immunol. 8, 1001-7
Interleukin 15 (IL-15) and IL-2, which promote the survival of memory CD8(+) T cells and regulatory T cells, respectively, bind receptor complexes that share beta- and gamma-signaling subunits. Receptor specificity is provided by unique, nonsignaling alpha-subunits. Whereas IL-2 receptor-alpha (IL-2Ralpha) is expressed together in cis with the beta- and gamma-subunits on T cells and B cells, IL-15Ralpha is expressed in trans on antigen-presenting cells. Here we present a 1.85-Å crystal structure of the human IL-15-IL-15Ralpha complex. The structure provides insight into the molecular basis of the specificity of cytokine recognition and emphasizes the importance of water in generating this very high-affinity complex. Despite very low IL-15-IL-2 sequence homology and distinct receptor architecture, the topologies of the IL-15-IL-15Ralpha and IL-2-IL-2Ralpha complexes are very similar. Our data raise the possibility that IL-2, like IL-15, might be capable of being presented in trans in the context of its unique receptor alpha-chain.
Key figure: Comparison of a modeled IL-15 signaling complex and the quaternary IL-2 signaling complex
Magenta, IL-15; cyan, IL-15Rα; green, IL-2Rβ; yellow, γc; blue, IL-2; red, IL-2Rα. (a) Two orthogonal views of the IL-15–IL-15Rα complex modeled with IL-2Rβ and γc. (b) The quaternary IL-2 receptor complex (Protein Data Bank accession code, 2b5i). ‘C’, positions of the carboxyl terminus of the α-subunit of each complex.