Structural Linkage Between Ligand Discrimination and Receptor Activation by Type I Interferons

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Aug 23

PMID 21854986

Citations 181

Authors

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

Affiliations

Soon will be listed here.

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.

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