Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines

Abstract

Interleukin 20 (IL-20) is a pleotropic IL-10 family cytokine that protects epithelial surfaces from pathogens. However, dysregulated IL-20 signaling is implicated in several human pathologies including psoriasis, rheumatoid arthritis, atherosclerosis, and osteoporosis. IL-20, and related cytokines IL-19 and IL-24, designated IL-20 subfamily cytokines (IL-20SFCs), induce cellular responses through an IL-20R1/IL-20R2 (type I) receptor heterodimer, whereas IL-20 and IL-24 also signal through the IL-22R1/IL-20R2 (type II) receptor complex. The crystal structure of the IL-20/IL-20R1/IL-20R2 complex reveals how type I and II complexes discriminate cognate from noncognate ligands. The structure also defines how the receptor-cytokine interfaces are affinity tuned to allow distinct signaling through a receptor complex shared by three different ligands. Our results provide unique insights into the complexity of IL-20SFC signaling that may be critical in the design of mechanistic-based inhibitors of IL-20SFC-mediated inflammatory disease.

The crystal structure of zebrafish IL-22 reveals an evolutionary, conserved structure highly similar to that of human IL-22

“…10 Type I IFNs in both mammals and fish are structurally distinct from the remainder of the class II cytokines, with the most notable difference being the F helix, which is straight in type I IFNs, while it bends almost 901 in all other class II cytokines. 4,7,10,11 An expansion of the class II cytokine system seems to have taken place largely during the Cambrian explosion when vertebrates diverged from basal chordates. In the protochordate Ciona intestinalis, two proteins showing similarities to class II cytokines receptors have been found, 2 although the ligands are still unknown.…”

“…Structures have been reported for several human members of this family, namely IL-22, IL-10, IL-19, IL-20, several type I IFNs, type II IFNs and one type III IFN (IFNl3). [4][5][6][7][8][9][10] They are all a-helical bundle-like proteins with six structural elements named A to F. Elements A, C, D, E and F are a-helices, whereas element B is more variable and contains a b-sheet harpin 7,10 in some members. The protein core is formed by four helices (A, C, D and F) in up-up-down-down orientation.…”

Identification of the Glycosaminoglycan Binding Site of Interleukin-10 by NMR Spectroscopy

“…Because the ternary IL-10 receptor complex could not be crystallized so far, only the structure of IL-10 in complex with its receptor chain 1 (IL-10R1) is known as of today. However, the structure of the related IL-20 receptor complex was solved recently (73). IL-10 and IL-20 belong to the same cytokine family and have a high structural similarity.…”

Interleukin-20 Receptor Expression in the Trabecular Meshwork and Its Implication in Glaucoma

“…IL-20R2 is a cytokine receptor that is involved in signaling by the IL-10 family cytokines, IL-19, IL-20, and IL-24. 49 IL-20 and IL-24 can signal through both heterodimeric receptor types, but IL-19 signals only through the type I complex (Fig. 1).…”

“…Previous studies have shown that IL-20R2 binds to the ligand, which then recruits IL-20R1 and heterodimerization occurs. 30 Since T104M sits at a site critical for ligand binding, 49 it is likely that cytokine binding and heterodimerization is disrupted. The T104M mutation could disrupt signaling that is initiated by all 3 cytokines.…”