Creation of Interferon-α8 Mutants with Amino Acid Substitutions Against Interferon-α Receptor-2 Binding Sites Using Phage Display System and Evaluation of Their Biologic Properties

Yamamoto, K.; Taniai, Madoka; Torigoe, Kakuji; Yamamoto, Sadaki; Arai, Norie; Suemoto, Yasuo; Yoshida, Keishiro; Okura, Takanori; Mori, Tetsuya; Fujioka, Noboru; Tanimoto, Tadao; Miyata, Manabu; Ariyasu, Harumi; Ushio, Chie; Fujii, Mitsukiyo; Ariyasu, Toshio; Ikeda, Masao; Ohta, Toshio; Kurimoto, Masashi; Fukuda, Shigeharu

doi:10.1089/jir.2008.0038

Cited by 8 publications

(13 citation statements)

References 24 publications

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“…The subtleties that govern these responses remain unclear (27)(28)(29)(30)(31). Sequence alignment of mIFNε with mIFNβ, mIFNα1 and hIFNα2 reveals the degree of homology of the IFNs within the known IFNAR1 and IFNAR2 binding interfaces, suggesting differences in the way these IFNs might interact with their receptors ( Supplementary Fig S3).…”

Section: Discussionmentioning

confidence: 99%

Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ

Stifter

Matthews

Mangan

et al. 2018

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ

Stifter

Matthews

Mangan

et al. 2018

Journal of Biological Chemistry

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“…Yamamoto et al . selected by phage display IFNα8 variants that differ by 100‐fold in their antiviral potency on amnionic FL challenged with Sindbis virus versus LS 174 T cells challenged with VSV. This finding suggests that yet unknown factors tune the specific antiviral potency (in addition to binding affinity).…”

Section: Systematic Correlation Of Binding Affinities With Ifn Activimentioning

confidence: 99%

“…The low activity of IFNa1 is consistent with its low receptor binding affinity, whereas the relative high antiviral activity of IFNa17 is surprising (83), as its binding affinity is similar to IFNa2. Yamamoto et al (79) selected by phage display IFNa8 variants that differ by 100-fold in their antiviral potency on amnionic FL challenged with Sindbis virus versus LS 174 T cells challenged with VSV. This finding suggests that yet unknown factors tune the specific antiviral potency (in addition to binding affinity).…”

Section: Systematic Correlation Of Binding Affinities With Ifn Activimentioning

confidence: 99%

Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation

Piehler

Thomas

García

et al. 2012

Immunological Reviews

204

225

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Summary Type I interferons (IFNs) form a network of homologous cytokines that bind to a shared, heterodimeric cell surface receptor and engage signaling pathways that activate innate and adaptive immune responses. The ability of IFNs to mediate differential responses through the same cell surface receptor has been subject of a controversial debate and has important medical implications. During the past decade, a comprehensive insight into the structure, energetics, and dynamics of IFN recognition by its two-receptor subunits, as well as detailed correlations with their functional properties on the level of signal activation, gene expression, and biological responses were obtained. All type I IFNs bind the two-receptor subunits at the same sites and form structurally very similar ternary complexes. Differential IFN activities were found to be determined by different lifetimes and ligand affinities toward the receptor subunits, which dictate assembly and dynamics of the signaling complex in the plasma membrane. We present a simple model, which explains differential IFN activities based on rapid endocytosis of signaling complexes and negative feedback mechanisms interfering with ternary complex assembly. More insight into signaling pathways as well as endosomal signaling and trafficking will be required for a comprehensive understanding, which will eventually lead to therapeutic applications of IFNs with increased efficacy.

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“…Compensating mutations on the IFNAR2 binding site demonstrated that the increased antiproliferative activity is a result of the stabilization of the ternary complex, and not due to tighter binding specifically to either one of the receptors [18*]. Other interferon agonists have been developed, including a 13 mer peptide [33], a consensus alpha-interferon [34], and an IFNα8 mutant optimized to bind tighter to IFNAR2 [35]. However, none of them reaches the activity level of either IFNβ or the YNS mutant.…”

Section: Type I Interferonsmentioning

confidence: 99%

Cytokine–receptor interactions as drug targets

Schreiber

Walter

2010

Current Opinion in Chemical Biology

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Cytokines are essential proteins that exert potent control over entire cell populations to fight infections and other pathologies, but can by themselves cause disease. Therefore, cytokine related drugs act either by stimulating or blocking their activities. Our knowledge of the structures of cytokine-receptor complexes, the biophysical basis of their binding, and their mode of biological activation has substantially increased in recent years. This knowledge has been translated into new drugs and drug candidates. This review summarizes our current understanding of the receptormediated activity of cytokines, their relation to health and disease, and the agents in use to activate and block their actions.Cytokines, such as interleukins (IL-) and interferons (IFN), are secreted proteins that carry intra-and inter-cellular signals that regulate the immune response to pathogens or other pathological conditions. For their function, cytokines must bind to specific extracellular receptors. Some cytokines, such as the type I interferons, have dedicated receptor chains (IFNAR1 and 2). However, other cytokines bind to both dedicated and shared receptors [1]. Two examples of cytokines that bind shared receptors are IL-4 and IL-13, which bind combinations of IL-4Rα, γ c and IL-13Rα [2*], and the different modes of interaction of GP130/CNTF-Rα/LIF-R with CNTF versus GP130/IL-6Rα with IL-6 [3*]. A combination of structural biology and biophysical methods has provided detailed information on many cytokine-receptor complexes. These studies have revealed that one receptor chain often functions as the "binding" receptor, exhibiting nM affinity, while the other receptor functions as the "signaling" receptor making only weak (μM affinity) interactions within the cytokine receptor complex.The mechanism of cytokine-mediated receptor activation remains controversial. One idea is that cytokine receptors are pre-assembled, or pre-concentrated on the cell surface, and activation occurs by structural changes in the receptors upon ligand binding. A competing model suggests that cytokine receptors are dispersed within a region of the membrane and cytokine binding "oligomerizes" the receptors. A major issue is the role of structural rearrangement versus receptor aggregation upon cytokine binding. FRET and other experiments have shown pre-assembly of the receptor chains for IL-5 [4*], IFNγR1 [5], GP130 [6], IL-10R1 [7] and others. In addition to pre-assembly of receptor chains, it was also suggested that some of the receptors are clustered on the membrane, facilitating rapid complex formation and cellular signaling. A good example for this concept is provided by Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process err...

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Creation of Interferon-α8 Mutants with Amino Acid Substitutions Against Interferon-α Receptor-2 Binding Sites Using Phage Display System and Evaluation of Their Biologic Properties

Cited by 8 publications

References 24 publications

Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ

Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ

Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation

Cytokine–receptor interactions as drug targets

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