Mapping human interferon-alpha (IFN-α2) binding determinants of the type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras

Lisa A. Goldman, Elizabeth Cali Cutrone, Anju Dang, Xiaoming Hao, Jin Kyu Lim, Jerome A. Langer

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Type I interferons bind to a common receptor (IFNAR), composed of two transmembrane polypeptides, IFNAR-I and IFNAR-2. Although human IFNAR-I has a weak intrinsic affinity for human Type I interferons (IFNs), bovine IFNAR-I binds human Type I IFNs with moderate (nM) affinity, and can be conveniently used to investigate the regions of IFNAR-I involved in ligand binding. We have constructed 14 bovine/human IFNAR-1 chimeras by exchanging homologous subdomains in the extracellular portion of the receptor. These chimeras were expressed at very high levels on COS cells, and their ability to bind HuIFN- α2 was measured. No single bovine subdomain substituted into human IFNAR-1 could confer moderate-affinity ligand binding on the resulting chimera. Simultaneous substitution of bovine IFNAR-1 subdomains 2 and 3 for the homologous human subdomains resulted in a dramatic increase in the binding of IFN-α2, suggesting that critical determinants for moderate-affinity ligand binding by BoIFNAR-1 reside in these two subdomains. Bovine subdomains 1 and/or 4 each further enhanced IFN-α2 binding in the presence of bovine subdomains 2 and 3. Thus, the binding interactions of BoIFNAR-1 with IFNs appears to be more complex than that of other class II cytokine receptors with their ligands.

Original languageEnglish
Pages (from-to)13003-13010
Number of pages8
JournalBiochemistry
Volume37
Issue number37
DOIs
StatePublished - 15 Sep 1998

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