Nanoscale membrane curvature sorts lipid phases and alters lipid diffusion

Woodward, Xinxin; Javanainen, Matti; Fábián, Balázs; Kelly, Christopher V.

doi:10.1016/j.bpj.2023.01.001

Cited by 5 publications

(5 citation statements)

References 66 publications

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“…We consistently observed actin fibers in the TIRF-averaged images of membrane proteins, which was surprising for non-Manuscript submitted to Biophysical Journal 13 actin-binding membrane proteins like GFP-GPI, PMT-mEGFP, and EGFR ΔABD -mEGFP. This phenomenon suggests that actin cytoskeleton-induced membrane morphology may play a role, which would be consistent with recent reports that membrane proteins can accumulate in regions of increased membrane curvature (80)(81)(82)(83)(84). The visibility of these fibers decreases with increased penetration depth, supporting the idea that these structures are seen at the membrane (albeit at a lower contrast than seen with actin-binding proteins) and are, thus, a membrane property.…”

Section: Discussionsupporting

confidence: 90%

EGFR does not directly interact with cortical actin: A SRRF’n’TIRF Study

Pandey,

Wohland

2024

Preprint

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The epidermal growth factor receptor (EGFR) governs pivotal signaling pathways in cell proliferation and survival, with mutations implicated in numerous cancers. The organization of EGFR on the plasma membrane (PM) is influenced by the lipids and the cortical actin (CA) cytoskeleton. Despite the presence of a putative actin-binding domain (ABD) spanning 13 residues, a direct interaction between EGFR and CA has not been definitively established. While disrupting the cytoskeleton can impact EGFR behavior, suggesting a connection, the influence of the static actin cytoskeleton has been found to be indirect. Here, we investigate the potential interaction between EGFR and CA, as well as the extent to which CA regulates EGFR's distribution on the PM using SRRF'n'TIRF, a spatiotemporal super-resolution microscopy technique that provides sub-100 nm resolution and ms-scale dynamics from the same dataset. To label CA, we constructed PMT-mEGFP-F-tractin, which combines an inner leaflet targeting domain PMT, fluorescent probe mEGFP, and the actin-binding protein Ftractin. In addition to EGFR-mEGFP, we included two control constructs: a) an ABD deletion mutant, EGFR-ΔABD-mEGFP serving as a negative control, and b) EGFRmApple-F-tractin, where F-tractin is fused to the C-terminus of EGFR-mApple, serving as the positive control. We find that EGFR-mEGFP and EGFR-ΔABD-mEGFP show similar membrane dynamics, implying that EGFR-mEGFP dynamics and organization are independent of CA. EGFR dynamics show CA dependence when F-tractin is anchored to the cytoplasmic tail. Together, our results demonstrate that EGFR does not directly interact with the CA in its resting and activated state.

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Section: Discussionsupporting

confidence: 90%

EGFR does not directly interact with cortical actin: A SRRF’n’TIRF Study

Pandey,

Wohland

2024

Preprint

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“…The associated entrance and escape permeabilities (eq 1) also differ from one another (6) where c in and c out are the reference concentrations inside and outside the liposome, as indicated in Figure 2.…”

Section: ■ Methodsmentioning

confidence: 99%

“…Nanosized drug delivery systems have been used to facilitate the delivery of drugs to the therapeutic targets in the body and to improve their therapeutic efficiency . Liposomes are spherical lipid-based carriers which may encapsulate drugs and reduce the drugs’ unwanted side effects. − Physical parameters such as bilayer composition and membrane curvature can significantly affect the liposome stability. − …”

Section: Introductionmentioning

confidence: 99%

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes

Davoudi,

Raemdonck,

Braeckmans

et al. 2023

J. Chem. Inf. Model.

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Liposomes are considered as advanced drug delivery systems for cancer treatment. A generation of pH-sensitive liposomes is being developed that use fatty acids (FAs) as a trigger for drug release in tumor tissues. However, FAs are also known to enhance permeability, and it is unclear whether FAs in liposomes may cause drug leakage or premature drug release. The passive permeability of the drug through the membrane of the liposome is thus a crucial factor for timely drug delivery. To investigate how the curvature and lipid composition of liposomes affect their passive permeability, coarse-grained molecular dynamics were performed. The permeability was determined with a counting method. Flat bilayers and three liposomes with varying diameters were studied, which had varying lipid compositions of dipalmitoylphosphatidylcholine, cholesterol, and deprotonated or neutral saturated FAs. The investigated permeants were water and two other small permeants, which have different free energy profiles (solubility) across the membrane. First, for the curvature effect, our results showed that curvature increases the water permeability by reducing the membrane thickness. The permeability increase for water is about a factor of 1.7 for the most curved membranes. However, a high curvature decreases permeability for permeants with free energy profiles that are a mix of wells and barriers in the headgroup region of the membrane. Importantly, the type of experimental setup is expected to play a dominant role in the permeability value, i.e., whether permeants are escaping or entering the liposomes. Second, for the composition effect, FAs decrease both the area per lipid (APL) and the membrane thickness, resulting in permeability increases of up to 55%. Cholesterol has a similar effect on the APL but has the opposite impact on membrane thickness and permeability. Therefore, FAs and cholesterol have opposing effects on permeability, with cholesterol’s effect being slightly stronger in our simulated bilayers. As all permeability values were well within a factor of 2, and with liposomes usually being larger and less curved in experimental applications, it can be concluded that the passive drug release from a pH-sensitive liposome does not seem to be significantly affected by the presence of FAs.

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“…12 Moreover, they can both also sense curvature, leading to spatial sorting with functional implications. 13,14 Adequate modeling 15,16 and analysis 17−20 of such nonplanar lipid bilayers requires the development of algorithms that take into account the geometry of the membrane. 6 A particularly fascinating property impacted by membrane curvature is the lateral diffusion of membrane components, which has a direct influence on the interpretation of experimental results obtained from techniques such as Fluorescence Correlation Spectroscopy (FCS) and Single Particle Tracking (SPT) that often assume planar geometries.…”

mentioning

confidence: 99%

“…In these processes, curvature is generated by both lipids and proteins . Moreover, they can both also sense curvature, leading to spatial sorting with functional implications. , …”

mentioning

confidence: 99%

Diffusion Analyses along Mean and Gaussian-Curved Membranes with CurD

Fábián,

Javanainen

2024

J. Phys. Chem. Lett.

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Curved cellular membranes are both abundant and functionally relevant. While novel tomography approaches reveal the structural details of curved membranes, their dynamics pose an experimental challenge. Curvature especially affects the diffusion of lipids and macromolecules, yet neither experiments nor continuum models distinguish geometric effects from those caused by curvature-induced changes in membrane properties. Molecular simulations could excel here, yet despite community interest toward curved membranes, tools for their analysis are still lacking. Here, we satisfy this demand by introducing CurD, our novel and openly available implementation of the Vertex-oriented Triangle Propagation algorithm to the study of lipid diffusion along membranes with mean and/or Gaussian curvature. This approach, aided by our highly optimized implementation, computes geodetic distances significantly faster than conventional implementations of path-finding algorithms. Our tool, applied to coarse-grained simulations, allows for the first time the analysis of curvature effects on diffusion at size scales relevant to physiological processes such as endocytosis. Our analyses with different membrane geometries reveal that Gaussian curvature plays a surprisingly small role on lipid motion, whereas mean curvature; i.e., the packing of lipid headgroups largely dictates their mobility.

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Nanoscale membrane curvature sorts lipid phases and alters lipid diffusion

Cited by 5 publications

References 66 publications

EGFR does not directly interact with cortical actin: A SRRF’n’TIRF Study

EGFR does not directly interact with cortical actin: A SRRF’n’TIRF Study

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes

Diffusion Analyses along Mean and Gaussian-Curved Membranes with CurD

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