TY - JOUR
T1 - Structural linkage between ligand discrimination and receptor activation by Type i interferons
AU - Thomas, Christoph
AU - Moraga, Ignacio
AU - Levin, Doron
AU - Krutzik, Peter O.
AU - Podoplelova, Yulia
AU - Trejo, Angelica
AU - Lee, Choongho
AU - Yarden, Ganit
AU - Vleck, Susan E.
AU - Glenn, Jeffrey S.
AU - Nolan, Garry P.
AU - Piehler, Jacob
AU - Schreiber, Gideon
AU - Garcia, K. Christopher
PY - 2011/8/19
Y1 - 2011/8/19
N2 - 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. PaperFlick:
AB - 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. PaperFlick:
UR - http://www.scopus.com/inward/record.url?scp=80051983083&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.06.048
DO - 10.1016/j.cell.2011.06.048
M3 - Article
C2 - 21854986
AN - SCOPUS:80051983083
SN - 0092-8674
VL - 146
SP - 621
EP - 632
JO - Cell
JF - Cell
IS - 4
ER -
