The IFN-?-IFN-?R1-IL-10R? Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity.

ABSTRACT: Type III interferons (IFN-?s) signal through a heterodimeric receptor complex composed of the IFN-?R1 subunit, specific for IFN-?s, and interleukin-10R? (IL-10R?), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10R? for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-? variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10R? uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.

SUBMITTER: Mendoza JL 

PROVIDER: S-EPMC5510750 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature