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: 33.12). 08/2011; 146(4):621-32. DOI: 10.1016/j.cell.2011.06.048
Source: PubMed

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 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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    • "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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    ABSTRACT: Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):653-61. DOI:10.1016/j.chom.2015.04.005 · 12.19 Impact Factor
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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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    ABSTRACT: Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to “tune” signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems.
    Cell 03/2015; 160:1-13. DOI:10.1016/j.cell.2015.02.011 · 33.12 Impact Factor
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    • "For example, binding of NGF or NT3 (also known as NTF3) to the TrkA receptor (NTRK1) has common but also different biological effects that correlate with different ligand-induced receptor membrane mobility and internalization (Marchetti et al., 2013). One other example is provided by the Type I interferons (16 different forms), which elicit different physiological responses through the same heterodimeric receptors IFNAR1 and IFNAR2 (Thomas et al., 2011). Interferons bind to this receptor through common 'anchor points' that are interspersed among ligand-specific interactions that tune ligand affinities, a mechanism referred to as 'ligand proofreading'. "
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