Flexible regions govern promiscuous binding of IL-24 to receptors IL-20R1 and IL-22R1
Jiří Zahradník, Lucie Kolářová, Yoav Peleg, Petr Kolenko, Silvie Svidenská, Tatsiana Charnavets, Tamar Unger, Joel L. Sussman, and Bohdan Schneider [1]
Molecular Tour
Interleukin 24 (IL-24) is cytokine, member of Interleukin 10 family. It forms an IL-20 subfamily with IL-19, IL-20, IL-22 because all these interleukins use the common class II cytokine receptor subunits and have similarities in biological functions [1]. IL-24 signals via two heterodimeric receptor complexes IL-22R1/IL-20R2 and IL-20R1/IL-20R2 and activates the STAT3 and STAT1 signaling (fig.1) [2, 3].
IL-24 is associated with multiple diseases, including the promotion and amplification of inflammatory responses during autoimmune and chronic inflammation [1], psoriasis-like skin inflammation [4], epidermal inflammation induced by stresses [5], inflammatory bowel disease [6, 7], and also with host defense during bacterial infection [8]. Some studies suggest anti-cancer activities that increased the interest in this molecule.
One of the stable variants (IL-24B) was crystallized, its structure solved at 1.3 Å resolution and deposited to PDB under the code 6gg1. This structure together with the recently published crystal structure of the ternary complex of IL-24 fused to IL-22R1 and co-expressed with IL-20R2 (PDB ID 6df3, [13]) allowed us to analyze the role of the mutated amino acid residues protein stability, flexibility, and binding to the cognate receptors (fig.2). Based on the analysis, we expressed a series of variants back engineered from the PROSS designed variant by changing the critical residues back to their wild types. We revealed that re-introduction of a single IL-24 wild type residue (T198) to the patch interacting with receptors 1 restored 80 % of the binding affinity and signaling capacity accompanied by an acceptable drop in the protein stability by 9°C.
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References
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