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Nat Commun. 2017 Jul 14;8:15976. doi: 10.1038/ncomms15976.

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments.

Author information

1
Department of Biology, University of Osnabrück, Barbarastr. 11, 49076 Osnabrück, Germany.
2
Howard Hughes Medical Institute, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305-5345, USA.
3
Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305-5345, USA.
4
Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs Institute, University of Würzburg, Julius-von Sachs Platz 2, 97082 Würzburg, Germany.
5
Physics of Life Processes, Leiden Institute of Physics, Leiden University, Niels Bohrweg 2, 2333 AC Leiden, The Netherlands.

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.

PMID:
28706306
PMCID:
PMC5519985
DOI:
10.1038/ncomms15976
[Indexed for MEDLINE]
Free PMC Article

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