Ligand-induced Type II Interleukin-4 Receptor Dimers Are Sustained by Rapid Re-association Within Plasma Membrane Microcompartments

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Jul 15

PMID 28706306

Citations 16

Authors

David Richter

Ignacio Moraga

Hauke Winkelmann

Oliver Birkholz

Stephan Wilmes

Markos Schulte

Michael Kraich

Hella Kenneweg

Oliver Beutel

Philipp Selenschik

Dirk Paterok

Martynas Gavutis

Thomas Schmidt

K Christopher Garcia

Thomas D Muller

Jacob Piehler

Affiliations

Soon will be listed here.

Abstract

The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.

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