Differential Receptor Subunit Affinities of Type I Interferons Govern Differential Signal Activation

Autor: Gilles Uzé, Jacob Piehler, Martynas Gavutis, Jacques Martal, Eva Jaks
Přispěvatelé: Défenses antivirales et antitumorales (DAA), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)
Rok vydání: 2007
Předmět:
MESH: Interferon Alfa-2a
MESH: Signal Transduction
MESH: Interferon Type I
MESH: Mutation
Lipid Bilayers
Plasma protein binding
Interferon alpha-2
Biology
Ligands
Models
Biological
Protein–protein interaction
MESH: Protein Structure
Tertiary
Structure-Activity Relationship
03 medical and health sciences
MESH: Structure-Activity Relationship
0302 clinical medicine
Structural Biology
Cell surface receptor
MESH: Ligands
MESH: Protein Binding
Humans
Structure–activity relationship
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Receptor
Molecular Biology
Ternary complex
Receptors
Interferon
030304 developmental biology
MESH: Receptors
Interferon
0303 health sciences
MESH: Humans
MESH: Lipid Bilayers
MESH: Models
Biological
Interferon-alpha
Recombinant Proteins
Transmembrane protein
Protein Structure
Tertiary
Biochemistry
Interferon Type I
Mutation
Biophysics
Signal transduction
Protein Binding
Signal Transduction
030215 immunology
Zdroj: Journal of Molecular Biology
Journal of Molecular Biology, Elsevier, 2007, 366 (2), pp.525-39. ⟨10.1016/j.jmb.2006.11.053⟩
ISSN: 0022-2836
1089-8638
DOI: 10.1016/j.jmb.2006.11.053
Popis: Type I interferons (IFNs) elicit antiviral, antiproliferative and immunmodulatory responses by binding to a shared cell surface receptor comprising the transmembrane proteins ifnar1 and ifnar2. Activation of differential response patterns by IFNs has been observed, suggesting that members of the family play different roles in innate immunity. The molecular basis for differential signaling has not been identified yet. Here, we have investigated the recognition of various IFNs including several human IFNalpha species, human IFNomega and human IFNbeta as well as ovine IFNtau2 by the receptor subunits in detail. Binding to the extracellular domains of ifnar1 (ifnar1-EC) and ifnar2 (ifnar2-EC) was monitored in real time by reflectance interference and total internal reflection fluorescence spectroscopy. For all IFNs investigated, competitive 1:1 interaction not only with ifnar2-EC but also with ifnar1-EC was shown. Furthermore, ternary complex formation was studied with ifnar1-EC and ifnar2-EC tethered onto solid-supported membranes. These analyses confirmed that the signaling complexes recruited by IFNs have very similar architectures. However, differences in rate and affinity constants over several orders of magnitude were observed for both the interactions with ifnar1-EC and ifnar2-EC. These data were correlated with the potencies of ISGF3 activation, antiviral and anti-proliferative activity on 2fTGH cells. The ISGF3 formation and antiviral activity correlated very well with the binding affinity towards ifnar2. In contrast, the affinity towards ifnar1 played a key role for antiproliferative activity. A striking correlation was observed for relative binding affinities towards ifnar1 and ifnar2 with the differential antiproliferative potency. This correlation was confirmed by systematically engineering IFNalpha2 mutants with very high differential antiproliferative potency.
Databáze: OpenAIRE
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