Artikel ; Online: Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists.
2008 Band 47, Heft 46, Seite(n) 12018–12027
Abstract: Type I interferons (IFNs) are multifunctional cytokines that activate cellular responses by binding a common receptor consisting of two subunits, IFNAR-1 and IFNAR-2. Although the binding of IFNs to IFNAR-2 is well characterized, the binding to the lower ...
Abstract | Type I interferons (IFNs) are multifunctional cytokines that activate cellular responses by binding a common receptor consisting of two subunits, IFNAR-1 and IFNAR-2. Although the binding of IFNs to IFNAR-2 is well characterized, the binding to the lower affinity IFNAR-1 remains less well understood. Previous reports identified a region of human IFN-alpha2 on the B and C helices ("site 1A": N65, L80, Y85, Y89) that plays a key role in binding IFNAR-1 and contributes strongly to differential activation by various type I IFNs. The current studies demonstrate that residues on the D helix are also involved in IFNAR-1 binding. In particular, residue 120 (Arg in IFN-alpha2; Lys in IFN-alpha2/alpha1) appears to be a "hot-spot" residue: substitution by alanine significantly decreased biological activity, and the charge-reversal mutation of residue 120 to Glu caused drastic loss of antiviral and antiproliferative activity for both IFN-alpha2 and IFN-alpha2/alpha1. Mutations in residues of helix D maintained their affinity for IFNAR-2 but had decreased affinity for IFNAR-1. Single-site or multiple-site mutants in the IFNAR-1 binding site that had little or no detectable in vitro biological activity were capable of blocking in vitro antiviral and antiproliferative activity of native IFN-alpha2; i.e., they are type I IFN antagonists. These prototype IFN antagonists can be developed further for possible therapeutic use in systemic lupus erythematosus, and analogous molecules can be designed for use in animal models. |
---|---|
Mesh-Begriff(e) | Amino Acid Substitution ; Animals ; Binding Sites/genetics ; Cattle ; Disease Models, Animal ; Humans ; Interferon-alpha/antagonists & inhibitors ; Interferon-alpha/chemistry ; Interferon-alpha/genetics ; Interferon-alpha/metabolism ; Lupus Erythematosus, Systemic/drug therapy ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/metabolism ; Mice ; Protein Binding/genetics ; Protein Structure, Secondary/genetics ; Receptor, Interferon alpha-beta/chemistry ; Receptor, Interferon alpha-beta/genetics ; Receptor, Interferon alpha-beta/metabolism |
Chemische Substanzen | IFNAR1 protein, human ; IFNAR2 protein, human ; Ifnar1 protein, mouse ; Ifnar2 protein, mouse ; Interferon-alpha ; Receptor, Interferon alpha-beta (156986-95-7) |
Sprache | Englisch |
Erscheinungsdatum | 2008-11-18 |
Erscheinungsland | United States |
Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1108-3 |
ISSN | 1520-4995 ; 0006-2960 |
ISSN (online) | 1520-4995 |
ISSN | 0006-2960 |
DOI | 10.1021/bi801588g |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
Zusatzmaterialien
Kategorien
Verfügbar in ZB MED Köln/Königswinter
Zs.A 217: Hefte anzeigen | Standort: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Über subito bestellen
Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.