title: Structural linkage between ligand discrimination and receptor activation by type I interferons.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomas
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraga
authors.forename: Doron
authors.initials: D
authors.lastname: Levin
authors.forename: Peter O
authors.initials: PO
authors.lastname: Krutzik
authors.forename: Yulia
authors.initials: Y
authors.lastname: Podoplelova
authors.forename: Angelica
authors.initials: A
authors.lastname: Trejo
authors.forename: Choongho
authors.initials: C
authors.lastname: Lee
authors.forename: Ganit
authors.initials: G
authors.lastname: Yarden
authors.forename: Susan E
authors.initials: SE
authors.lastname: Vleck
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Glenn
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007370:Interferon Type I / Q000737:chemistry* / Q000378:metabolism; D016898:Interferon-alpha / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D008024:Ligands; D017471:Receptors, Interferon; C063743:interferon omega 1