Differences in activity between alpha and beta type I interferons explored by mutational analysis

• Published in: The Journal of biological chemistry 1998-04, Vol.273 (14), p.8003-8008
• Main Authors: Runkel, L, Pfeffer, L, Lewerenz, M, Monneron, D, Yang, C H, Murti, A, Pellegrini, S, Goelz, S, Uzé, G, Mogensen, K
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biochemistry, Molecular Biology; Cattle; DNA Mutational Analysis; Humans; Interferon-alpha - chemistry; Interferon-alpha - genetics; Interferon-alpha - metabolism; Interferon-beta - chemistry; Interferon-beta - genetics; Interferon-beta - metabolism; Life Sciences; Molecular Sequence Data; Point Mutation; Structure-Activity Relationship
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.14.8003

Type I interferon (IFN) subtypes alpha and beta share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, alpha and beta IFNs exhibit key differences in several biological properties. For example, IFN-beta, but not IFN-alpha, 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-beta with point mutations and compared them to wild-type IFN-beta in assays that distinguish alpha and beta IFN subtypes. IFN-beta 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-alpha8) increased the cross-species activity of the mutant IFN-betas on bovine cells to a level comparable to that of human IFN-alphas. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtype-specific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-alpha mutations. The effects of these mutations on IFN-beta activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.