[Protein Structure and Folding] Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION

[admin]

[Protein Structure and Folding] Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION

Interleukin (IL)-15 is a pleiotropic cytokine that plays a pivotal role in both innate and adaptive immunity. IL-15 is unique among cytokines due to its participation in a trans signaling mechanism in which IL-15 receptor (IL-15R) from one subset of cells presents IL-15 to neighboring IL-2Rβ/c-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15R. The structure reveals that the receptor-binding epitope of IL-15 adopts a unique conformation, which, together with amino acid substitutions, permits specific interactions with IL-15R that account for the exceptionally high affinity of the IL-15·IL-15R complex. Interestingly, analysis of the topology of IL-15 and IL-15R at the IL-15·IL-15R interface suggests that IL-15 should be capable of participating in a cis signaling mechanism similar to that of the related cytokine IL-2. Indeed, we present biochemical data demonstrating that IL-15 is capable of efficiently signaling in cis through IL-15R and IL-2Rβ/c expressed on the surface of a single cell. Based on our data we propose that cis presentation of IL-15 may be important in certain biological contexts and that flexibility of IL-15R permits IL-15 and its three receptor components to be assembled identically at the ligand-receptor interface whether IL-15 is presented in cis or trans. Finally, we have gained insights into IL-15·IL-15R·IL-2Rβ·c quaternary complex assembly through the use of molecular modeling.