Structural linkage between ligand discrimination and receptor activation by Type i interferons

Christoph Thomas; Ignacio Moraga; Doron Levin; Peter O. Krutzik; Yulia Podoplelova; Angelica Trejo; Choongho Lee; Ganit Yarden; Susan E. Vleck; Jeffrey S. Glenn; Garry P. Nolan; Jacob Piehler; Gideon Schreiber; K. Christopher Garcia

doi:10.1016/j.cell.2011.06.048

Structural linkage between ligand discrimination and receptor activation by Type i interferons

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

Department of Biomolecular Sciences

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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. PaperFlick:

Original language	English
Pages (from-to)	621-632
Number of pages	12
Journal	Cell
Volume	146
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2011.06.048
State	Published - 19 Aug 2011

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2011.06.048

Cite this

@article{ec257e34b9144df09907a2f8889091b1,

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. PaperFlick:",

author = "Christoph Thomas and Ignacio Moraga and Doron Levin and Krutzik, \{Peter O.\} and Yulia Podoplelova and Angelica Trejo and Choongho Lee and Ganit Yarden and Vleck, \{Susan E.\} and Glenn, \{Jeffrey S.\} and Nolan, \{Garry P.\} and Jacob Piehler and Gideon Schreiber and Garcia, \{K. Christopher\}",

note = "International Human Frontier Science Program Organization; European Community [223608]; [NIH-RO1-AI51321]; [NIH-RO1-AI087917]We thank Natalia Goriatcheva for expert technical assistance, the staff at SSRL and ALS for their assistance, and David Canner for preparing the Proteopedia pages. K. C. G. is an Investigator of the Howard Hughes Medical Institute. This work was also supported by NIH-RO1-AI51321 (K. C. G.) and NIH-RO1-AI087917 (J.S.G.), C. T. is supported by a long-term postdoctoral fellowship of the International Human Frontier Science Program Organization. G. S. and J.P. are supported by the European Community's FP7/2007-2013 under GA no. 223608 (IFNaction).",

year = "2011",

month = aug,

day = "19",

doi = "10.1016/j.cell.2011.06.048",

language = "الإنجليزيّة",

volume = "146",

pages = "621--632",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "4",

}

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

N1 - International Human Frontier Science Program Organization; European Community [223608]; [NIH-RO1-AI51321]; [NIH-RO1-AI087917]We thank Natalia Goriatcheva for expert technical assistance, the staff at SSRL and ALS for their assistance, and David Canner for preparing the Proteopedia pages. K. C. G. is an Investigator of the Howard Hughes Medical Institute. This work was also supported by NIH-RO1-AI51321 (K. C. G.) and NIH-RO1-AI087917 (J.S.G.), C. T. is supported by a long-term postdoctoral fellowship of the International Human Frontier Science Program Organization. G. S. and J.P. are supported by the European Community's FP7/2007-2013 under GA no. 223608 (IFNaction).

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 - مقالة

SN - 0092-8674

VL - 146

SP - 621

EP - 632

JO - Cell

JF - Cell

IS - 4

ER -

Structural linkage between ligand discrimination and receptor activation by Type i interferons

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this