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

Runkel, L.; Pfeffer, L.; Lewerenz, M.; Monneron, D.; Yang, C. H.; Murti, A.; Pellegrini, S.; Goelz, S.; Uze, G.; Mogensen, K.

Journal of Biological Chemistry

1998-04-03 / vol 273 / pages 8003-8008


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-alpha 8) increased the cross-species activity of the mutant IFN-beta s on bovine cells to a level comparable to that of human IFN-alpha s. 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.



expression; phosphorylation; molecular-cloning; protein-tyrosine kinase; cells; signaling pathway; crystal-structure; receptor-binding; recombinant; subunit

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