Catching a complex for optimal signaling

Dirk M Zajonc

doi:10.1074/jbc.h119.010823

Abstract

Agonistic antibodies are powerful tools to dimerize receptors in the absence of ligand binding, but high-fidelity receptor activation requires that these antibodies accurately recapitulate the native dimeric state. Spangler et al. employ a clever approach to select for antibodies that bind a specific IL-4Rα/γc heterodimeric complex in its native signaling conformation, leading to a monovalent "stapler," a single-chain variable fragment (scFv) that binds at the dimerization interface. This powerful approach can be further exploited for a variety of homo- or heterodimeric receptors to achieve signaling, especially in the absence of endogenous ligand.

Highlights

Cells frequently use transmembrane receptors to convey information from the extracellular environment to the intracellular space
IL-4 can bind to IL-4R␣/IL-13R␣1 complexes, leading to different signaling outcomes
IL-2R␣ itself does not signal, but its expression level appears to correlate with IL-2 sensitivity of the cells

Summary

Introduction

Cells frequently use transmembrane receptors to convey information from the extracellular environment to the intracellular space. IL-4 can bind to IL-4R␣/IL-13R␣1 complexes, leading to different signaling outcomes. The approach from Spangler et al cleverly targets these two cases in a way that overcomes the limitation of traditional antibody-mediated receptor dimerization, by trapping the IL-4 receptor heterodimer in its native signaling state before screening a naive antibody library for high-affinity binders [2].

Results

Conclusion