Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons
Autor(en): | 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 |
Stichwörter: | AFFINITY; ALPHA; BINDING-SITE; Biochemistry & Molecular Biology; Cell Biology; COMPLEX REVEALS; CRYSTAL-STRUCTURE; GAMMA; IFN-ALPHA-2; IFNAR1; MUTANT; MUTATIONAL ANALYSIS | Erscheinungsdatum: | 2011 | Herausgeber: | CELL PRESS | Journal: | CELL | Volumen: | 146 | Ausgabe: | 4 | Startseite: | 621 | Seitenende: | 632 | Zusammenfassung: | 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 IFN alpha 2 and IFN omega 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. |
ISSN: | 00928674 | DOI: | 10.1016/j.cell.2011.06.048 |
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geprüft am 28.04.2024