Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling
| Autor: | André Leier, Stephan Wilmes, Ignacio Moraga, Jacob Piehler, Changjiang You, K. Christopher Garcia, Tatiana T. Marquez-Lago, Christian Richter |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Dimer hop diffusion plasma membrane organization Nanotechnology single molecule tracking Receptor Interferon alpha-beta 02 engineering and technology Cell Line Protein–protein interaction protein-protein interaction Diffusion Cytokine receptor signaling 03 medical and health sciences chemistry.chemical_compound spatial stochastic modeling Bacterial microcompartment Quantum Dots Humans Compartment (development) Receptor Research Articles Multidisciplinary Plasma membrane organization Cell Membrane SciAdv r-articles Cell Biology 021001 nanoscience & nanotechnology 030104 developmental biology Membrane Microscopy Fluorescence chemistry Quantum dot Biophysics Cytokines Protein Multimerization 0210 nano-technology Research Article type I interferon receptor Signal Transduction |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | Single-molecule tracking and spatial stochastic modeling reveal receptor dimer stabilization by nanoscale confinement zones. The interaction dynamics of signaling complexes is emerging as a key determinant that regulates the specificity of cellular responses. We present a combined experimental and computational study that quantifies the consequences of plasma membrane microcompartmentalization for the dynamics of type I interferon receptor complexes. By using long-term dual-color quantum dot (QD) tracking, we found that the lifetime of individual ligand-induced receptor heterodimers depends on the integrity of the membrane skeleton (MSK), which also proved important for efficient downstream signaling. By pair correlation tracking and localization microscopy as well as by fast QD tracking, we identified a secondary confinement within ~300-nm-sized zones. A quantitative spatial stochastic diffusion-reaction model, entirely parameterized on the basis of experimental data, predicts that transient receptor confinement by the MSK meshwork allows for rapid reassociation of dissociated receptor dimers. Moreover, the experimentally observed apparent stabilization of receptor dimers in the plasma membrane was reproduced by simulations of a refined, hierarchical compartment model. Our simulations further revealed that the two-dimensional association rate constant is a key parameter for controlling the extent of MSK-mediated stabilization of protein complexes, thus ensuring the specificity of this effect. Together, experimental evidence and simulations support the hypothesis that passive receptor confinement by MSK-based microcompartmentalization promotes maintenance of signaling complexes in the plasma membrane. |
| Databáze: | OpenAIRE |
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