Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons

SummaryType I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand “anchor points” interspersed among ligand-specific interactions that “tune” the relative IFN-binding affinities, in an apparent extracellular “ligand proofreading” mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (19002 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (245 K)Download as PowerPoint slideHighlights► The type I interferon receptor complex is a novel heterotrimeric architecture ► Type I interferons share a common docking mode for receptor binding ► Ligand discrimination occurs through distinct energetics of shared receptor contacts ► Differential IFN signaling is modulated by ligand recognition chemistries