The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity.
Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rβ (IL-10Rβ), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rβ for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rβ uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Juan L
JL
Mendoza
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
William M
WM
Schneider
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Hans-Heinrich
HH
Hoffmann
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Koen
K
Vercauteren
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kevin M
KM
Jude
Department of Medicine, Division of Gastroenterology and Hepatology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA Stanford University School of Medicine, Stanford, CA 94305, USA.
Anming
A
Xiong
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ignacio
I
Moraga
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Tim M
TM
Horton
Department of Medicine, Division of Gastroenterology and Hepatology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA Stanford University School of Medicine, Stanford, CA 94305, USA.
Jeffrey S
JS
Glenn
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.
Ype P
YP
de Jong
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Charles M
CM
Rice
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
K Christopher
KC
Garcia
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D005434:Flow Cytometry; D006801:Humans; D007372:Interferons / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000276:immunology*; D020349:Surface Plasmon Resonance
D017471:Receptors, Interferon; D053701:Receptors, Interleukin-10; D007372:Interferons