Actin-induced perturbation of PS lipid–cholesterol interaction: A possible mechanism of cytoskeleton-based regulation of membrane organization

Garg, Sumit; Tang, Jay X.; Rühe, Jürgen; Naumann, Christoph

doi:10.1016/j.jsb.2009.04.001

Cited by 23 publications

(22 citation statements)

References 45 publications

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“…This behavior is remarkably similar to that described by one-dimensional phase diagrams of cholesterol and other lipids in model membranes and likely reflects a role for PS in driving mixing or demixing of lipid assemblies. In support of this interpretation, biophysical studies also suggest a complex role for PS in membrane lateral heterogeneity (45,58), where inclusion of actin significantly alters the moles percent of PS required to induce phase separation and highlights a specific role for actin-PS interactions in driving membrane heterogeneity (45). Similarly, our observations on cell PM, coupled with mathematical simulations, now strongly implicate actin-PS interactions in regulating membrane lateral heterogeneity in intact cells (44,59).…”

Section: Discussionsupporting

confidence: 72%

“…Such specificity implies that in addition to electrostatics, determinants such as lipid packing geometry and lipid cross-sectional area may constrain the interactions between K-Ras and different acidic lipids. Similar levels of selectivity occur in model bilayers and molecular dynamic (MD) simulations, where negatively charged lipids, such as PS and PA, display different capabilities to mediate actin-induced changes in membrane organization (43,45).…”

Section: Discussionmentioning

confidence: 84%

“…PS lateral distribution between mobile and immobile pools is dynamically regulated in the PM (27,45). To predict how changing PS mobile pool size may affect K-Ras nanoclustering and KRas/H-Ras segregation, we next simulated the model under conditions of reduced actin or reduced caveolae.…”

Section: Ras Nanoclusters Have Different Lipid Compositions But All mentioning

confidence: 99%

“…6a and b, we performed equivalent experiments in vivo. BHK cells were briefly treated with latrunculin to disrupt cortical actin and to release actin-immobilized PS into a mobile pool (27,45). An increase in mobile PS was confirmed by FRAP experiments on BHK cells, where the TF-PS mobile fraction increased by ϳ31% after a 5-min treatment with latrunculin ( Fig.…”

Section: Ras Nanoclusters Have Different Lipid Compositions But All mentioning

confidence: 99%

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Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters

Zhou

Luan

Rodkey

et al. 2014

Molecular and Cellular Biology

126

245

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b Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters, however, has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions, indicating that Ras proteins engage in isoform-selective lipid sorting and accounting for different signal outputs from different Ras isoforms. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence, Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experimentation reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important previously unexplored opportunities for signal integration and signal processing. H-, N-, and K-Ras are small GTPases that operate as molecular switches to regulate cell growth, proliferation, and differentiation (1, 2). H-, N-, and K-Ras comprise nearly identical G domains (amino acids 1 to 165), which bind guanine nucleotides and interact with effectors and exchange factors, but they contain highly divergent C-terminal hypervariable regions (HVRs) (3, 4). The HVR undergoes posttranslational processing to attach a membrane anchor, which consists of a C-terminal S-farnesyl cysteine carboxylmethyl ester (common to all Ras proteins) and mono-palmitoylation of N-Ras, di-palmitoylation of H-Ras, and the presence of a polylysine domain in K-Ras (5-8). Ras proteins are distributed heterogeneously over the plasma membrane (PM) in a combination of immobile nanoclusters and freely diffusing monomers (9). A nanocluster comprises ϳ7 Ras proteins, has a radius of ϳ9 nm, and has an estimated lifetime of 0.5 to 1 s (10, 11). Nanocluster formation is essential for high-fidelity signal transmission (11-16). As a direct consequence of the different lipid anchors and different residues in the flanking HVR and G domain, which directly participate in membrane binding, N-, H-, and K-Ras assemble into spatially nonoverlapping nanoclusters, with further lateral segregation into nonoverlapping GDP and GTP nanoclusters (11,(16)(17)(18)(19)(20)(21)(22)(23).Ras isoforms exhibit different effector activation profiles (1). To account for isoform-specific signal output, Ras ...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 84%

Section: Ras Nanoclusters Have Different Lipid Compositions But All mentioning

confidence: 99%

Section: Ras Nanoclusters Have Different Lipid Compositions But All mentioning

confidence: 99%

See 2 more Smart Citations

Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters

Zhou

Luan

Rodkey

et al. 2014

Molecular and Cellular Biology

126

245

View full text Add to dashboard Cite

show abstract

“…Cholesterol is a component in the presynaptic and synaptic vesicle membrane, and it has been reported to promote demixing of PS in PC:PS bilayers (32)(33)(34)(35). To examine the effect of cholesterol, C2B, C2AB, and C2A were added to vesicles containing PC:PS:cholesterol (55:25:20) along with 1% NBD-PS.…”

Section: Evidence For Ps Sequestration Is Obtained In a Range Of Lipimentioning

confidence: 99%

Synaptotagmin 1 Modulates Lipid Acyl Chain Order in Lipid Bilayers by Demixing Phosphatidylserine

Lai

Tamm

Ellena

et al. 2011

Journal of Biological Chemistry

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Synaptotagmin 1 (syt1) functions as the Ca 2؉ sensor in neuronal exocytosis, and it has been proposed to act by modulating lipid bilayer curvature. Here we examine the effect of the two C2 domains (C2A and C2B) of syt1 on membrane lipid order and lateral organization. In mixtures of phosphatidylcholine and phosphatidylserine (PS), attenuated total internal reflection Fourier transform infrared spectroscopy indicates that a fragment containing both domains (C2AB) or C2B alone disorders the lipid acyl chains, whereas the C2A domain has little effect upon chain order. Two observations suggest that these changes reflect a demixing of PS. First, the changes in acyl chain order are reversed at higher protein concentration; second, selective lipid deuteration demonstrates that the changes in lipid order are associated only with the PS component of the bilayer. Independent evidence for lipid demixing is obtained from fluorescence selfquenching of labeled lipid and from natural abundance 13 C NMR, where heteronuclear single quantum correlation spectra reveal Ca 2؉ -dependent chemical shift changes for PS, but not for phosphatidylcholine, in the presence of the syt1 C2 domains. The ability of syt1 to demix PS is observed in a range of lipid mixtures that includes cholesterol, phosphatidylethanolamine, and varied PS content. These data suggest that syt1 might facilitate SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors)-mediated membrane fusion by phase separating PS, a process that is expected to locally buckle bilayers and disorder lipids due to the curvature tendencies of PS.

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Plasma Membrane—Cortical Cytoskeleton Interactions: A Cell Biology Approach with Biophysical Considerations

Kapùs

Janmey

2013

Comprehensive Physiology

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From a biophysical standpoint, the interface between the cell membrane and the cytoskeleton is an intriguing site where a "two-dimensional fluid" interacts with an exceedingly complex three-dimensional protein meshwork. The membrane is a key regulator of the cytoskeleton, which not only provides docking sites for cytoskeletal elements through transmembrane proteins, lipid binding-based, and electrostatic interactions, but also serves as the source of the signaling events and molecules that control cytoskeletal organization and remolding. Conversely, the cytoskeleton is a key determinant of the biophysical and biochemical properties of the membrane, including its shape, tension, movement, composition, as well as the mobility, partitioning, and recycling of its constituents. From a cell biological standpoint, the membrane-cytoskeleton interplay underlies--as a central executor and/or regulator--a multitude of complex processes including chemical and mechanical signal transduction, motility/migration, endo-/exo-/phagocytosis, and other forms of membrane traffic, cell-cell, and cell-matrix adhesion. The aim of this article is to provide an overview of the tight structural and functional coupling between the membrane and the cytoskeleton. As biophysical approaches, both theoretical and experimental, proved to be instrumental for our understanding of the membrane/cytoskeleton interplay, this review will "oscillate" between the cell biological phenomena and the corresponding biophysical principles and considerations. After describing the types of connections between the membrane and the cytoskeleton, we will focus on a few key physical parameters and processes (force generation, curvature, tension, and surface charge) and will discuss how these contribute to a variety of fundamental cell biological functions.

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Actin-induced perturbation of PS lipid–cholesterol interaction: A possible mechanism of cytoskeleton-based regulation of membrane organization

Cited by 23 publications

References 45 publications

Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters

Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters

Synaptotagmin 1 Modulates Lipid Acyl Chain Order in Lipid Bilayers by Demixing Phosphatidylserine

Plasma Membrane—Cortical Cytoskeleton Interactions: A Cell Biology Approach with Biophysical Considerations

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