Author/Authors :
Christoph Thomas، نويسنده , , Ignacio Moraga، نويسنده , , Doron Levin، نويسنده , , Peter O. Krutzik، نويسنده , , Yulia Podoplelova، نويسنده , , Angelica Trejo، نويسنده , , Choongho Lee، نويسنده , , Ganit Yarden، نويسنده , , Susan E. Vleck، نويسنده , , Jeffrey S. Glenn، نويسنده , , Garry P. Nolan، نويسنده , , Jacob Piehler، نويسنده , , Gideon Schreiber and Jacob Anglister، نويسنده , , K. Christopher Garcia، نويسنده ,
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.
