Article

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: 32.4). 08/2011; 146(4):621-32. DOI:10.1016/j.cell.2011.06.048 pp.621-32
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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    Article: Type 1 interferons and the virus-host relationship: a lesson in détente .
    Adolfo García-Sastre, Christine A Biron
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    ABSTRACT: The interface between an infectious agent and its host represents the ultimate battleground for survival: The microbe must secure a niche for replication, whereas the host must limit the pathogen's advance. Among the host's arsenal of antimicrobial factors, the type 1 interferons (IFNs) induce potent defense mechanisms against viruses and are key in the host-virus standoff. Viruses have evolved multiple tricks to avoid the immediate antiviral effects of IFNs and, in turn, hosts have adapted use of this innate cytokine system to galvanize multiple additional layers of immune defense. The plasticity that exists in these interactions provides us with a lesson in détente.
    Science 06/2006; 312(5775):879-82. · 31.20 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

anchor points
 
cell-surface receptors
 
collectively control signal initiation
 
complex stability
 
conserved receptor-ligand
 
cytokine receptor superfamily
 
different type
 
downstream gene expression patterns
 
human type
 
innate immunity
 
ligand proofreading
 
ligand-induced conformational change
 
ligand-specific interactions
 
modulates biological activity
 
receptor internalization rates
 
Receptor-ligand cross-reactivity
 
recognition modes
 
regulating differential STAT phosphorylation profiles
 
relative IFN-binding affinities
 
respective receptor recognition chemistries