Receptor dimer stabilization By hierarchical plasma membrane microcompartments regulates cytokine signaling

Changjiang You, Tatiana T. Marquez-Lago, Christian Paolo Richter, Stephan Wilmes, Ignacio Moraga, K. Christopher Garcia, André Leier (Lead / Corresponding author), Jacob Piehler (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
17 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere1600452
Number of pages12
JournalScience Advances
Volume2
Issue number12
DOIs
Publication statusPublished - 2 Dec 2016

Keywords

  • Cytokine receptor signaling
  • type I interferon receptor
  • plasma membrane organization
  • hop diffusion
  • protein-protein interaction
  • single molecule tracking
  • spatial stochastic modeling

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