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Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions.

ABSTRACT: While Rho GTPases are indispensible regulators of cellular polarity, the mechanisms underlying their anisotropic activation at membranes have been elusive. Using the budding yeast Cdc42 GTPase module, which includes a guanine nucleotide exchange factor (GEF) Cdc24 and the scaffold Bem1, we find that avidity generated via multivalent anionic lipid interactions is a critical mechanistic constituent of polarity establishment. We identify basic cluster (BC) motifs in Bem1 that drive the interaction of the scaffold-GEF complex with anionic lipids at the cell pole. This interaction appears to influence lipid acyl chain ordering, thus regulating membrane rigidity and feedback between Cdc42 and the membrane environment. Sequential mutation of the Bem1 BC motifs, PX domain, and the PH domain of Cdc24 lead to a progressive loss of cellular polarity stemming from defective Cdc42 nanoclustering on the plasma membrane and perturbed signaling. Our work demonstrates the importance of avidity via multivalent anionic lipid interactions in the spatial control of GTPase activation.

SUBMITTER: Meca J

PROVIDER: S-EPMC6356062 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions.

Meca Julien J Massoni-Laporte Aurélie A Martinez Denis D Sartorel Elodie E Loquet Antoine A Habenstein Birgit B McCusker Derek D

The EMBO journal 20181217 3

While Rho GTPases are indispensible regulators of cellular polarity, the mechanisms underlying their anisotropic activation at membranes have been elusive. Using the budding yeast Cdc42 GTPase module, which includes a guanine nucleotide exchange factor (GEF) Cdc24 and the scaffold Bem1, we find that avidity generated via multivalent anionic lipid interactions is a critical mechanistic constituent of polarity establishment. We identify basic cluster (BC) motifs in Bem1 that drive the interaction ...[more]

PMID: 30559330

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Project description:The targeted delivery of nanoparticle carriers holds tremendous potential to transform the detection and treatment of diseases. A major attribute of nanoparticles is the ability to form multiple bonds with target cells, which greatly improves the adhesion strength. However, the multivalent binding of nanoparticles is still poorly understood, particularly from a dynamic perspective. In previous experimental work, we studied the kinetics of nanoparticle adhesion and found that the rate of detachment decreased over time. Here, we have applied the adhesive dynamics simulation framework to investigate binding dynamics between an antibody-conjugated, 200-nm-diameter sphere and an ICAM-1-coated surface on the scale of individual bonds. We found that nano adhesive dynamics (NAD) simulations could replicate the time-varying nanoparticle detachment behavior that we observed in experiments. As expected, this behavior correlated with a steady increase in mean bond number with time, but this was attributed to bond accumulation only during the first second that nanoparticles were bound. Longer-term increases in bond number instead were manifested from nanoparticle detachment serving as a selection mechanism to eliminate nanoparticles that had randomly been confined to lower bond valencies. Thus, time-dependent nanoparticle detachment reflects an evolution of the remaining nanoparticle population toward higher overall bond valency. We also found that NAD simulations precisely matched experiments whenever mechanical force loads on bonds were high enough to directly induce rupture. These mechanical forces were in excess of 300 pN and primarily arose from the Brownian motion of the nanoparticle, but we also identified a valency-dependent contribution from bonds pulling on each other. In summary, we have achieved excellent kinetic consistency between NAD simulations and experiments, which has revealed new insights into the dynamics and biophysics of multivalent nanoparticle adhesion. In future work, we will leverage the simulation as a design tool for optimizing targeted nanoparticle agents.

Dataset Information

Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions.

Publications

Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions.

Similar Datasets

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