Differences in activity between alpha and beta type I interferons explored by mutational analysis
| Autor: | Danielle Monneron, Lawrence M. Pfeffer, Aruna Murti, Laura Runkel, Chuan He Yang, Malte Lewerenz, Gilles Uzé, Susan Goelz, Sandra Pellegrini, Knud Erik Mogensen |
|---|---|
| Přispěvatelé: | Institut Pasteur [Paris], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Défenses antivirales et antitumorales (DAA), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1) |
| Rok vydání: | 1998 |
| Předmět: |
protein-tyrosine kinase molecular-cloning signaling pathway crystal-structure receptor-binding recombinant cells expression subunit phosphorylation
Mutant DNA Mutational Analysis Molecular Sequence Data Alpha (ethology) Biology Biochemistry 03 medical and health sciences Structure-Activity Relationship Cell surface receptor Interferon medicine Animals Humans Point Mutation [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Amino Acid Sequence Receptor Molecular Biology 030304 developmental biology Genetics 0303 health sciences Point mutation 030302 biochemistry & molecular biology Interferon-alpha Cell Biology Interferon-beta Molecular biology Cattle Signal transduction Janus kinase medicine.drug |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 1998, 273 (14), pp.8003--8008. ⟨10.1074/jbc.273.14.8003⟩ Journal of Biological Chemistry, 1998, 273 (14), pp.8003--8008. ⟨10.1074/jbc.273.14.8003⟩ |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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