Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments
Autor(en): | Richter, David Moraga, Ignacio Winkelmann, Hauke Birkholz, Oliver Wilmes, Stephan Schulte, Markos Kraich, Michael Kenneweg, Hella Beutel, Oliver Selenschik, Philipp Paterok, Dirk Gavutis, Martynas Schmidt, Thomas Garcia, K. Christopher Mueller, Thomas D. Piehler, Jacob |
Stichwörter: | CELL-SURFACE; ERYTHROPOIETIN RECEPTOR; GROWTH-HORMONE RECEPTOR; LIVING CELLS; MODEL MEMBRANES; Multidisciplinary Sciences; POLYMER-SUPPORTED MEMBRANES; RESONANCE ENERGY-TRANSFER; Science & Technology - Other Topics; SINGLE-MOLECULE TECHNIQUES; T-CELLS; TRANSMEMBRANE PROTEINS | Erscheinungsdatum: | 2017 | Herausgeber: | NATURE PUBLISHING GROUP | Journal: | NATURE COMMUNICATIONS | Volumen: | 8 | Zusammenfassung: | 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. |
ISSN: | 20411723 | DOI: | 10.1038/ncomms15976 |
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geprüft am 28.04.2024