Dynamics in the plasma membrane: how to combine fluidity and order
TL;DR: The basic concepts of Brownian diffusion and lipid domain formation in model membranes are summarized and the development of ideas and tools in this field are tracked, outlining key results obtained on the dynamic processes at work in membrane structure and assembly.
Abstract: Cell membranes are fascinating supramolecular aggregates that not only form a barrier between compartments but also harbor many chemical reactions essential to the existence and functioning of a cell. Here, it is proposed to review the molecular dynamics and mosaic organization of the plasma membrane, which are thought to have important functional implications. We will first summarize the basic concepts of Brownian diffusion and lipid domain formation in model membranes and then track the development of ideas and tools in this field, outlining key results obtained on the dynamic processes at work in membrane structure and assembly. We will focus in particular on findings made using fluorescent labeling and imaging procedures to record these dynamic processes. We will also discuss a few examples showing the impact of lateral diffusion on cell signal transduction, and outline some future methodological challenges which must be met before we can answer some of the questions arising in this field of research.
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TL;DR: In this article, the multifaceted role of lipids in endothelial mechanobiology and mechanisms of atherogenesis are discussed in a review, and changes in blood flow characteristics are detected by endothelial cells and affect their structure and function.
Abstract: Atherosclerosis is one of the most important problems in modern medicine. Its high prevalence and social significance determine the need for a better understanding of the mechanisms of the disease’s development and progression. Lipid metabolism and its disorders are one of the key links in the pathogenesis of atherosclerosis. Lipids are involved in many processes, including those related to the mechanoreception of endothelial cells. The multifaceted role of lipids in endothelial mechanobiology and mechanisms of atherogenesis are discussed in this review. Endothelium is involved in ensuring adequate vascular hemodynamics, and changes in blood flow characteristics are detected by endothelial cells and affect their structure and function.
15 citations
TL;DR: It is predicted that, depending on the density of membrane-bound proteins and the degree to which a single protein molecule can induce intrinsic mean curvature in the membrane, a range of membrane phase behaviour can be observed including two different modes of vesicle-bud nucleation and repressed membrane undulations.
Abstract: Using a recently developed multiscale simulation methodology, we describe the equilibrium behaviour of bilayer membranes under the influence of curvature-inducing proteins using a linearized elastic free energy model. In particular, we describe how the cooperativity associated with a multitude of protein–membrane interactions and protein diffusion on a membrane-mediated energy landscape elicits emergent behaviour in the membrane phase. Based on our model simulations, we predict that, depending on the density of membrane-bound proteins and the degree to which a single protein molecule can induce intrinsic mean curvature in the membrane, a range of membrane phase behaviour can be observed including two different modes of vesicle-bud nucleation and repressed membrane undulations. A state diagram as a function of experimentally tunable parameters to classify the underlying states is proposed.
15 citations
TL;DR: It is proposed that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β- secretase and could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.
Abstract: β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the β-secretase is present. In addition, membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.
15 citations
Cites background from "Dynamics in the plasma membrane: ho..."
...The present concept [49] of lipid rafts is that they are dynamic assemblies of sphingolipids, cholesterol and raft proteins that dissociate and associate on a rapid time-scale [47, 50]....
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TL;DR: The observation of local protein surface dynamics starts to be a useful tool to determine the contribution of intracellular and extracellular structures in organizing a plastic synapse.
Abstract: The precision of signal transmission in chemical synapses is highly dependent on the structural alignment between pre- and postsynaptic components. The thermal agitation of transmembrane signaling molecules by surrounding lipid molecules and activity-driven changes in the local protein interaction affinities indicate a dynamic molecular traffic of molecules within synapses. The observation of local protein surface dynamics starts to be a useful tool to determine the contribution of intracellular and extracellular structures in organizing a plastic synapse. Local rearrangements by lateral diffusion in the synaptic and perisynaptic membrane induce fast density changes of signaling molecules and enable the synapse to change efficacy in short time scales. The degree of lateral mobility is restricted by many passive and active interactions inside and outside the membrane. AMPAR at the glutamatergic synapse are the best explored receptors in this respect and reviewed here as an example molecule. In addition, transsynaptic adhesion molecule complexes also appear highly dynamically in the synapse and do further support the importance of local surface traffic in subcellular compartments like synapses.
14 citations
TL;DR: It is found that mobility probes nanometer-sized properties of the moving protein and its local environment, which may be subject to cell-to-cell variability, up to five-fold higher variability of the diffusion constant between cells compared to the uncertainty for the determination ofThe diffusion constant on a single cell.
Abstract: In recent years increasing evidence has been reported for the inherent heterogeneity of cell populations. Cell-to-cell variability was particularly found when analyzing protein expression patterns or the responses of cells to different stimuli. Yet, structural features – in particular below the resolution limit of light microscopy – have so far eluded in-depth statistical analysis. We report here for the first time a detailed investigation of the variations in protein mobility between nominally identical cells. Our reasoning was that mobility probes nanometer-sized properties of the moving protein and its local environment, which may be subject to cell-to-cell variability. Single-molecule tracking was employed to characterize the diffusion constant of the glycosylphosphatidylinositol- (GPI-) anchored protein CD59 and the transmembrane protein CD147 in the plasma membrane of T24 cells. Automated and tailored data analysis routines allowed for the analysis of the required large data sets: ∼200000 trajectories obtained on ∼350 cells were analyzed in total. We found up to five-fold higher variability of the diffusion constant between cells compared to the uncertainty for the determination of the diffusion constant on a single cell.
14 citations
References
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TL;DR: Results strongly indicate that the bivalent antibodies produce an aggregation of the surface immunoglobulin molecules in the plane of the membrane, which can occur only if the immunoglOBulin molecules are free to diffuse in the membrane.
Abstract: A fluid mosaic model is presented for the gross organization and structure of the proteins and lipids of biological membranes. The model is consistent with the restrictions imposed by thermodynamics. In this model, the proteins that are integral to the membrane are a heterogeneous set of globular molecules, each arranged in an amphipathic structure, that is, with the ionic and highly polar groups protruding from the membrane into the aqueous phase, and the nonpolar groups largely buried in the hydrophobic interior of the membrane. These globular molecules are partially embedded in a matrix of phospholipid. The bulk of the phospholipid is organized as a discontinuous, fluid bilayer, although a small fraction of the lipid may interact specifically with the membrane proteins. The fluid mosaic structure is therefore formally analogous to a two-dimensional oriented solution of integral proteins (or lipoproteins) in the viscous phospholipid bilayer solvent. Recent experiments with a wide variety of techniqes and several different membrane systems are described, all of which abet consistent with, and add much detail to, the fluid mosaic model. It therefore seems appropriate to suggest possible mechanisms for various membrane functions and membrane-mediated phenomena in the light of the model. As examples, experimentally testable mechanisms are suggested for cell surface changes in malignant transformation, and for cooperative effects exhibited in the interactions of membranes with some specific ligands. Note added in proof: Since this article was written, we have obtained electron microscopic evidence (69) that the concanavalin A binding sites on the membranes of SV40 virus-transformed mouse fibroblasts (3T3 cells) are more clustered than the sites on the membranes of normal cells, as predicted by the hypothesis represented in Fig. 7B. T-here has also appeared a study by Taylor et al. (70) showing the remarkable effects produced on lymphocytes by the addition of antibodies directed to their surface immunoglobulin molecules. The antibodies induce a redistribution and pinocytosis of these surface immunoglobulins, so that within about 30 minutes at 37 degrees C the surface immunoglobulins are completely swept out of the membrane. These effects do not occur, however, if the bivalent antibodies are replaced by their univalent Fab fragments or if the antibody experiments are carried out at 0 degrees C instead of 37 degrees C. These and related results strongly indicate that the bivalent antibodies produce an aggregation of the surface immunoglobulin molecules in the plane of the membrane, which can occur only if the immunoglobulin molecules are free to diffuse in the membrane. This aggregation then appears to trigger off the pinocytosis of the membrane components by some unknown mechanism. Such membrane transformations may be of crucial importance in the induction of an antibody response to an antigen, as well as iv other processes of cell differentiation.
7,790 citations
TL;DR: The new generations of qdots have far-reaching potential for the study of intracellular processes at the single-molecule level, high-resolution cellular imaging, long-term in vivo observation of cell trafficking, tumor targeting, and diagnostics.
Abstract: Research on fluorescent semiconductor nanocrystals (also known as quantum dots or qdots) has evolved over the past two decades from electronic materials science to biological applications. We review current approaches to the synthesis, solubilization, and functionalization of qdots and their applications to cell and animal biology. Recent examples of their experimental use include the observation of diffusion of individual glycine receptors in living neurons and the identification of lymph nodes in live animals by near-infrared emission during surgery. The new generations of qdots have farreaching potential for the study of intracellular processes at the single-molecule level, high-resolution cellular imaging, long-term in vivo observation of cell trafficking, tumor targeting, and diagnostics.
7,499 citations
"Dynamics in the plasma membrane: ho..." refers background in this paper
...The use of fluorescent quantum dots is emerging as a promising alternative to classical fluorescent tags (GFPs and organic fluorophores) (Michalet et al, 2005)....
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...…quantum yields, large molar extinction coefficients, size-dependent tunable emission and high photostability) make them appeal- &2006 European Molecular Biology Organization The EMBO Journal VOL 25 | NO 15 | 2006 3449 ing candidate tags for use with SDT (Dahan et al, 2003; Michalet et al, 2005)....
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TL;DR: This review looks at current methods for preparing QD bioconjugates as well as presenting an overview of applications, and concludes that the potential of QDs in biology has just begun to be realized and new avenues will arise as the ability to manipulate these materials improves.
Abstract: One of the fastest moving and most exciting interfaces of nanotechnology is the use of quantum dots (QDs) in biology. The unique optical properties of QDs make them appealing as in vivo and in vitro fluorophores in a variety of biological investigations, in which traditional fluorescent labels based on organic molecules fall short of providing long-term stability and simultaneous detection of multiple signals. The ability to make QDs water soluble and target them to specific biomolecules has led to promising applications in cellular labelling, deep-tissue imaging, assay labelling and as efficient fluorescence resonance energy transfer donors. Despite recent progress, much work still needs to be done to achieve reproducible and robust surface functionalization and develop flexible bioconjugation techniques. In this review, we look at current methods for preparing QD bioconjugates as well as presenting an overview of applications. The potential of QDs in biology has just begun to be realized and new avenues will arise as our ability to manipulate these materials improves.
5,875 citations
"Dynamics in the plasma membrane: ho..." refers background in this paper
...However, there is still a need to improve the functionalization of QD surfaces, the flexibility for bioconjugations and single irreversible molecular associations between individually tracked molecules (Medintz et al, 2005)....
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Book•
01 Jan 1983
TL;DR: This book is a lucid, straightforward introduction to the concepts and techniques of statistical physics that students of biology, biochemistry, and biophysics must know.
Abstract: This book is a lucid, straightforward introduction to the concepts and techniques of statistical physics that students of biology, biochemistry, and biophysics must know. It provides a sound basis for understanding random motions of molecules, subcellular particles, or cells, or of processes that depend on such motion or are markedly affected by it. Readers do not need to understand thermodynamics in order to acquire a knowledge of the physics involved in diffusion, sedimentation, electrophoresis, chromatography, and cell motility--subjects that become lively and immediate when the author discusses them in terms of random walks of individual particles.
3,041 citations
"Dynamics in the plasma membrane: ho..." refers background in this paper
...Brownian motion is a principle that applies to all biological systems (Berg, 1983): as the result of thermal agitation processes, molecules are constantly on the move, colliding with each other and bouncing back and forth (Figure 1)....
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...…plasma membrane dynamics Brownian motion, diffusion and membrane organization Brownian motion is a principle that applies to all biological systems (Berg, 1983): as the result of thermal agitation processes, molecules are constantly on the move, colliding with each other and bouncing back and…...
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TL;DR: A unified characterization of the best available FPs provides a useful guide in narrowing down the options for biological imaging tools.
Abstract: The recent explosion in the diversity of available fluorescent proteins (FPs) promises a wide variety of new tools for biological imaging. With no unified standard for assessing these tools, however, a researcher is faced with difficult questions. Which FPs are best for general use? Which are the brightest? What additional factors determine which are best for a given experiment? Although in many cases, a trial-and-error approach may still be necessary in determining the answers to these questions, a unified characterization of the best available FPs provides a useful guide in narrowing down the options.
2,933 citations
"Dynamics in the plasma membrane: ho..." refers background in this paper
...As the cDNA encoding the GFP was characterized, a wide variety of monomeric fluorescent proteins have provided attractive potential candidates for monitoring dynamic processes in which different molecular species are simultaneously involved (for a review, see Shaner et al, 2005)....
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