TY - JOUR
T1 - Receptor dimer stabilization By hierarchical plasma membrane microcompartments regulates cytokine signaling
AU - You, Changjiang
AU - Marquez-Lago, Tatiana T.
AU - Richter, Christian Paolo
AU - Wilmes, Stephan
AU - Moraga, Ignacio
AU - Garcia, K. Christopher
AU - Leier, André
AU - Piehler, Jacob
PY - 2016/12/2
Y1 - 2016/12/2
N2 - 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.
AB - 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.
KW - Cytokine receptor signaling
KW - type I interferon receptor
KW - plasma membrane organization
KW - hop diffusion
KW - protein-protein interaction
KW - single molecule tracking
KW - spatial stochastic modeling
UR - http://www.scopus.com/inward/record.url?scp=85024477432&partnerID=8YFLogxK
U2 - 10.1126/sciadv.1600452
DO - 10.1126/sciadv.1600452
M3 - Article
AN - SCOPUS:85024477432
VL - 2
JO - Science Advances
JF - Science Advances
SN - 2375-2548
IS - 12
M1 - e1600452
ER -