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

Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell (Impact Factor: 32.24). 08/2011; 146(4):621-32. DOI: 10.1016/j.cell.2011.06.048
Source: PubMed


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 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.

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

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    • "Structured analysis has revealed that functional differences between IFNs are linked to their unique receptor binding strengths and dissociation rates, which combine to determine their ability to induce conformational change in the receptor. These ultimately control signal generation and downstream gene expression (Piehler et al., 2012; Thomas et al., 2011). "
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    • "Cytokine receptor dimerization principally results in activation of intracellular, non-covalently associated Janus kinases (JAKs), which then activate the STAT pathway to modulate gene expression and ultimately determine cell fate (Ihle et al., 1995; O'Shea and Paul, 2010). Structures of cytokine-receptor ECD complexes from different systems have revealed a diverse range of molecular architectures and receptor dimer topologies that are compatible with signaling (Boulanger et al., 2003; de Vos et al., 1992; Hansen et al., 2008; LaPorte et al., 2008; Livnah et al., 1996; Ring et al., 2012; Syed et al., 1998; Thomas et al., 2011; Walter et al., 1995; Wang et al., 2005). This topological diversity is also apparent for dimeric RTK ECD complexes with their agonist ligands (Kavran et al., 2014; Lemmon and Schlessinger, 2010). "
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    • "It is likely that these opposing effects reflect cell type-specific differences in the activation of secondary or “non-canonical” signaling events and/or variations in the dominance of a specific type I IFN species. Indeed, individual type I IFN proteins vary in their ability to elicit specific responses and stimulation of different cell types can cause distinct signaling events (7, 8). "
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