Structural linkage between ligand discrimination and receptor activation by type I interferons |
| |
Authors: | Thomas Christoph Moraga Ignacio Levin Doron Krutzik Peter O Podoplelova Yulia Trejo Angelica Lee Choongho Yarden Ganit Vleck Susan E Glenn Jeffrey S Nolan Garry P Piehler Jacob Schreiber Gideon Garcia K Christopher |
| |
Institution: | 1 Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Department of Microbiology and Immunology, Baxter Lab in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA 3 Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA 4 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel 5 Division of Biophysics, University of Osnabrück, 49076 Osnabrück, Germany |
| |
Abstract: | Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor points" interspersed among ligand-specific interactions that "tune" the relative IFN-binding affinities, in an apparent extracellular "ligand proofreading" mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|