Recent results indicate that coherent models of how multiple interferons (IFN) are recognized and signal selectively through a common receptor are now feasible. A proposal is made that the IFN receptor, with its subunits IFNAR-1 and IFNAR-2, presents two separate ligand binding sites, and this double structure is both necessary and sufficient to ensure that the different IFN are recognized and can act selectively. The key feature is the duplication of the extracellular domain of the IFNAR-1 subunit and the configurational geometry that this imposes on the intracellular domains of the receptor subunits and their associated tyrosine kinases.

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Type I interferon (IFN) subtypes ␣ and ␤ share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, ␣ and ␤ IFNs exhibit key differences in several biological properties. For example, IFN-␤, but not IFN-␣, induces the association of tyrosine-phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor-associated, Janus kinase tyk2. To define the structural basis for these functional differences we produced human IFN-␤ with point mutations and compared them to wild-type IFN-␤ in assays that distinguish ␣ and ␤ IFN subtypes. IFN-␤ mutants with charged residues (N86K, N86E, or Y92D) introduced at two positions in the C helix lost the ability to induce the association of tyrosine-phosphorylated receptor chains and had reduced activity on tyk2-deficient cells. The combination of negatively charged residues N86E and Y92D (homologous with IFN-␣8) increased the cross-species activity of the mutant IFN-␤s on bovine cells to a level comparable to that of human IFN-␣s. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtypespecific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-␣ mutations. The effects of these mutations on IFN-␤ activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.The mammalian type I IFNs, 1 produced in response to viral infection and other inducers, are divided into ␣ and ␤ subtypes on the basis of their reactivity with antisera raised against IFNs derived, respectively, from leukocytes and fibroblasts (1). The human IFN-␣s are encoded by a family of at least 15 different genes, while IFN-␤ is the unique member of its subtype (2). Primary sequence comparison between the ␣ and ␤ subtypes reveal an approximately 50% amino acid homology, while the amino acid homologies between the IFN-␣ subtypes are approximately 80% (2, 3), reinforcing the division between IFN-␣ and -␤ subtypes.As the pleiotropic nature of these cytokines became apparent, with both subtypes eliciting a similar range of biological activities (3), differences between ␣ subtypes, and between IFN-␣ and -␤s, in potency and cell type specific activities were noted (4). In particular, IFN-␤ elicits a markedly higher antiproliferation response in some cell types such as (5), embryonal carcinoma, melanoma and melanocytes than do IFN-␣s (6, 7, and references therein). Higher potency of IFN-␤ in treatment of multiple sclerosis and certain cancers has been observed (7).The entire class of type I IFNs elicit their biological activities through engagement of a common cell surface receptor (8 -10). Two chains of the receptor, ifnar1 and ifnar2, both members of the type two cytokine receptor family, have been identified (11-15). Both components are necessary for function and in the absence of either there is neither...