The tertiary structure of γc cytokines dictates receptor sharing

The γc family of cytokines comprising interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-2 is an important group of 4-helix bundle cytokines that signals through receptors incorporating the common gamma chain (γc). These cytokines are involved in lymphocyte biology and their specific functions are contingent on binding to cognate receptor chains. Here, we examined the structural relationships between γc cytokines, aiming to understand the basis for receptor chain usage and sharing. To that end, we obtained tertiary structures of human and mouse γc cytokines plus two other related cytokines, IL-13 and TSLP, which share receptors with IL-4 and IL-7, respectively. Subsequently, we compared the cytokine 3D-structures introducing a structural similarity score that grouped γc cytokines in a manner that mirrored the relationships dictated by receptor sharing. Unlike previously thought, we identified that IL-9 is more closely related to IL-2 and IL-15 than to IL-7, which is actually the most distant member of the γc family of cytokines. Moreover, we found that all the members of the γc family of cytokines share the topology of short-chain 4-helix bundle cytokines but IL-7 that with TSLP has the topology of long-chain 4-helix bundle cytokines. We also carried out Maximun-Likehood and Bayesian phylogenetic analyses that supported these results at the amino acid sequence level. Overall, our findings are of paramount relevance to understand receptor sharing among γc cytokines and can lead to the discovery of new cytokine receptor partners.