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Journal:FEBS Journal:1
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<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | 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 | + | 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 <ref name="Rutz">PMID:25421700</ref>. 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 | + | IL-24 is associated with multiple diseases, including the promotion and amplification of inflammatory responses during autoimmune and chronic inflammation <ref name="Rutz">PMID:25421700</ref>, 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. | 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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2. Dumoutier L, Leemans C, Lejeune D, Kotenko SV & Renauld JC (2001) Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types, J Immunol 167, 3545-9. | 2. Dumoutier L, Leemans C, Lejeune D, Kotenko SV & Renauld JC (2001) Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types, J Immunol 167, 3545-9. | ||
Revision as of 11:45, 16 June 2019
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