Mutation of the IFNAR-1 receptor binding site of human IFN-α2 generates type I IFN competitive antagonists

Manjing Pan, Eyal Kalie, Brian J. Scaglione, Elizabeth S. Raveche, Gideon Schreiber, Jerome Langer

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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-α2 on the B and C helices ("site IA": 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-α2; Lys in IFN-α2/α1) 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-α2 and IFN-α2/α1. 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-α2; 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.

Original languageEnglish (US)
Pages (from-to)12018-12027
Number of pages10
JournalBiochemistry
Volume47
Issue number46
DOIs
StatePublished - Nov 18 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry

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