Title : Structural linkage between ligand discrimination and receptor activation by type I interferons
Abstract :
- Type 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 IFN ω 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
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