The fluid mosaic model of Singer and Nicolson (1972) is a commonly used representation of the cell membrane structure and dynamics. However a number of features, the result of four decades of ...research, must be incorporated to obtain a valid, contemporary version of the model. Among the novel aspects to be considered are: (i) the high density of proteins in the bilayer, that makes the bilayer a molecularly “crowded” space, with important physiological consequences; (ii) the proteins that bind the membranes on a temporary basis, thus establishing a continuum between the purely soluble proteins, never in contact with membranes, and those who cannot exist unless bilayer-bound; (iii) the progress in our knowledge of lipid phases, the putative presence of non-lamellar intermediates in membranes, and the role of membrane curvature and its relation to lipid geometry, (iv) the existence of lateral heterogeneity (domain formation) in cell membranes, including the transient microdomains known as rafts, and (v) the possibility of transient and localized transbilayer (flip-flop) lipid motion. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
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•The fluid mosaic model of membrane structure by Singer and Nicolson was published in 1972.•The model remains essentially valid.•However new and important data must be incorporated into the model.
Ceramides are sphingolipids containing a sphingosine or a related base, to which a fatty acid is linked through an amide bond. When incorporated into a lipid bilayer, ceramides exhibit a number of ...properties not shared by almost any other membrane lipid: Ceramides ( a) are extremely hydrophobic and thus cannot exist in suspension in aqueous media; ( b) increase the molecular order (rigidity) of phospholipids in membranes; ( c) give rise to lateral phase separation and domain formation in phospholipid bilayers; ( d) possess a marked intrinsic negative curvature that facilitates formation of inverted hexagonal phases; ( e) make bilayers and cell membranes permeable to small and large (i.e., protein-size) solutes; and ( f) promote transmembrane (flip-flop) lipid motion. Unfortunately, there is hardly any link between the physical studies reviewed here and the mass of biological and clinical studies on the effects of ceramides in health and disease.
Multiple data are available on the self-assembly of mixtures of bilayer-forming amphiphiles, particularly phospholipids and micelle-forming amphiphiles, commonly denoted detergents. The structure of ...such mixed assemblies has been thoroughly investigated, described in phase diagrams, and theoretically rationalized in terms of the balance between the large spontaneous curvature of the curvophilic detergent and the curvophobic phospholipids. In this critical review, we discuss the mechanism of this process and try to explain the actual mechanism involved in solubilization. Interestingly, membrane solubilization by some detergents is relatively slow and the common attribute of these detergents is that their trans-bilayer movement, commonly denoted flip-flop, is very slow. Only detergents that can flip into the inner monolayer cause relatively rapid solubilization of detergent-saturated bilayers. This occurs via the following sequence of events: 1), relatively rapid penetration of detergent monomers into the outer monolayer; 2), trans-membrane equilibration of detergent monomers between the two monolayers; 3), saturation of the bilayer by detergents and consequent permeabilization of the membrane; and 4), transition of the whole bilayer to thread-like mixed micelles. When the detergent cannot flip to the inner monolayer, the outer monolayer becomes unstable due to mass imbalance between the monolayers and inclusion of the curvophilic detergent molecules in a flat surface. Consequently, the outer monolayer forms mixed micellar structures within the outer monolayer. Shedding of these micelles into the aqueous solution results in partial solubilization. The consequent leakage of detergent into the liposome results in trans-membrane equilibration of detergent and subsequent micellization through the rapid bilayer-saturation mechanism.
•Membrane rafts have been proposed to be nm-sized, short-lived lipid-protein domains.•Methods that would allow visualizing such structures in vivo are only now beginning to emerge.•The raft concept ...maybe an oversimplification for a variety of nanostructures of heterogeneous sizes and functions.•It is wrong to equate rafts with detergent-resistant membrane fractions.•The term “raft” could be replaced with advantage by “nanodomain”.
The membrane raft hypothesis, proposed in 1997 by Simons and Ikonen, has played a paradoxical role in the history of biomembrane research. While it has generated a large amount of investigations, thus helping to increase our understanding of membranes, the object that gives name to the hypothesis, i.e. the raft itself, has been and still is an object of controversy, in which its very reality is often questioned. In this contribution I review the history of the hypothesis and its reception by membrane biologists, and summarize some of the valuable physico-chemical results that have been obtained while testing the raft hypothesis. To save a useful concept from its many misuses I propose that the expression “(transient) nanodomains” be employed instead of “rafts”.
The available data concerning the ability of ceramide and other simple sphingolipids to segregate laterally into rigid, gel-like domains in a fluid bilayer has been reviewed. Ceramides give rise to ...rigid ceramide-enriched domains when their N-acyl chain is longer than C12. The high melting temperature of hydrated ceramides, revealing a tight intermolecular interaction, is probably responsible for their lateral segregation. Ceramides compete with cholesterol for the formation of domains with lipids such as sphingomyelin or saturated phosphatidylcholines; under these conditions displacement of cholesterol by ceramide involves a transition from a liquid-ordered to a gel-like phase in the domains involved. When ceramide is generated
in situ by a sphingomyelinase, instead of being premixed with the other lipids, gel-like domain formation occurs as well, although the topology of the domains may not be the same, the enzyme causing clustering of domains that is not detected with premixed ceramide. Ceramide-1-phosphate is not likely to form domains in fluid bilayers, and the same is true of sphingosine and of sphingosine-1-phosphate. However, sphingosine does rigidify pre-existing gel domains in mixed bilayers.
Some of the simplest sphingolipids, namely sphingosine, ceramide, some closely related molecules (eicosasphingosine, phytosphingosine), and their phosphorylated compounds (sphingosine-1-phosphate, ...ceramide-1-phosphate), are potent metabolic regulators. Each of these lipids modifies in marked and specific ways the physical properties of the cell membranes, in what can be the basis for some of their physiological actions. This paper reviews the mechanisms by which these sphingolipid signals, sphingosine and ceramide in particular, are able to modify the properties of cell membranes.
Although detergents are routine tools in biomembrane research, their use remains empirical. We propose that solubilization is the result of a balance between two parameters: (i) the energy associated ...with bending of phospholipid monolayers into a curved micellar surface, and (ii) the energy associated with filling the void in the center of the resultant mixed micelle. In this review, we show that reliable data on the phase boundaries, and their dependence on various conditions, are consistent with this hypothesis, even if the data might have been interpreted differently. Although most of the experimental data discussed here were obtained with the non-ionic detergent Triton X-100, the conclusions should be applicable to a wide variety of detergents.
Some of the simplest sphingolipids, namely sphingosine, ceramide and their phosphorylated compounds sphingosine 1-phosphate (Sph-1-P) and ceramide 1-phosphate (Cer-1-P), are potent metabolic ...regulators. Each of these lipids modifies in marked and specific ways the physical properties of the cell membranes, in what can be the basis for some of their physiological actions. The present paper is an overview of the mechanisms by which these sphingolipid signals, sphingosine and ceramide, in particular, are able to modify the properties of cell membranes.
Aβ peptides are known to bind neural plasma membranes in a process leading to the deposit of Aβ-enriched plaques. These extracellular structures are characteristic of Alzheimer’s disease, the major ...cause of late-age dementia. The mechanisms of Aβ plaque formation and deposition are far from being understood. A vast number of studies in the literature describe the efforts to analyze those mechanisms using a variety of tools. The present review focuses on biophysical studies mostly carried out with model membranes or with computational tools. This review starts by describing basic physical aspects of lipid phases and commonly used model membranes (monolayers and bilayers). This is followed by a discussion of the biophysical techniques applied to these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, and molecular dynamics. The Methodological Section is followed by the core of the review, which includes a summary of important results obtained with each technique. The last section is devoted to an overall reflection and an effort to understand Aβ-bilayer binding. Concepts such as Aβ peptide membrane binding, adsorption, and insertion are defined and differentiated. The roles of membrane lipid order, nanodomain formation, and electrostatic forces in Aβ–membrane interaction are separately identified and discussed.
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