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

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. Müller and Jacob Piehler ()
Additional contact information
David Richter: University of Osnabrück
Ignacio Moraga: Howard Hughes Medical Institute, Stanford University School of Medicine
Hauke Winkelmann: University of Osnabrück
Oliver Birkholz: University of Osnabrück
Stephan Wilmes: University of Osnabrück
Markos Schulte: Julius-von-Sachs Institute, University of Würzburg
Michael Kraich: Julius-von-Sachs Institute, University of Würzburg
Hella Kenneweg: University of Osnabrück
Oliver Beutel: University of Osnabrück
Philipp Selenschik: University of Osnabrück
Dirk Paterok: University of Osnabrück
Martynas Gavutis: University of Osnabrück
Thomas Schmidt: Physics of Life Processes, Leiden Institute of Physics, Leiden University
K. Christopher Garcia: Howard Hughes Medical Institute, Stanford University School of Medicine
Thomas D. Müller: Julius-von-Sachs Institute, University of Würzburg
Jacob Piehler: University of Osnabrück

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15976

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