Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain

SummaryIL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 Å resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease.

► The crystal structure of the IL-10R2 is distinct from IL-10R1 and IL-22R1 chains
► IL-10R2 residues required for binding multiple cytokines have been identified
► Docking studies provide structures of the promiscuous recognition paradigm
► Class 1 and class 2 receptor common chains exhibit conserved binding epitopes