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Review
. 2011 Oct 1;3(10):a004697.
doi: 10.1101/cshperspect.a004697.

Membrane organization and lipid rafts

Kai Simons  1 , Julio L Sampaio
Affiliations
Review

Membrane organization and lipid rafts

Kai Simons et al. Cold Spring Harb Perspect Biol. .

Abstract

Cell membranes are composed of a lipid bilayer, containing proteins that span the bilayer and/or interact with the lipids on either side of the two leaflets. Although recent advances in lipid analytics show that membranes in eukaryotic cells contain hundreds of different lipid species, the function of this lipid diversity remains enigmatic. The basic structure of cell membranes is the lipid bilayer, composed of two apposing leaflets, forming a two-dimensional liquid with fascinating properties designed to perform the functions cells require. To coordinate these functions, the bilayer has evolved the propensity to segregate its constituents laterally. This capability is based on dynamic liquid-liquid immiscibility and underlies the raft concept of membrane subcompartmentalization. This principle combines the potential for sphingolipid-cholesterol self-assembly with protein specificity to focus and regulate membrane bioactivity. Here we will review the emerging principles of membrane architecture with special emphasis on lipid organization and domain formation.

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Figures

Figure 1.
Figure 1.
Lipid shape and supramolecular organization (polymorphism). Phospholipids can be classified as cylinders (e.g., PC), cones (e.g., PE), and inverted cones (e.g., lysophosphatidylcholine), depending on the relative volumes of their polar head groups and fatty acyl chains. The supramolecular organization of such molecules generates the widespread bilayer (or lamellar) structure, and the nonlamellar micellar and cubic phases.
Figure 2.
Figure 2.
Raft clustering and domain-induced budding. Before clustering, proteins associate with rafts (red) to various extents (1). Clustering is induced, for example, by the binding of a dimerizing protein (green) to a trans-membrane raft protein (2). The scaffolded raft-associated proteins coalesce into a raft cluster. Growth of the clustered raft domain beyond a critical size induces budding (3). Finally, a transport container consisting of raft components pinches off from the parent membrane by fission at the domain boundaries. Additional protein machinery will facilitate and regulate the budding process (4).
Figure 3.
Figure 3.
The tunable states of rafts. Resting-state rafts are dynamic, nanoscopic assemblies of raft lipids and proteins that are metastable (i.e., persist for a certain time [top]). The coupling between the outer and the inner leaflet is not well understood. Most raft proteins are either solely lipid-anchored (GPI-anchored in the exoplasmic [1] or doubly acylated in the cytoplasmic leaflet [2]), or they contain acyl chains in addition to their TMD (3). A fourth group could undergo a conformational change when partitioning into rafts (4) or following binding to glycosphingolipids (5). Following oligomerization of raft proteins by multivalent ligands (6) or cytoplasmic scaffolds (7), the small raft domains coalesce and become more stable. They may now contain more than one family of raft proteins. These small raft clusters would still have a size below the limits of light microscopic resolution, but could already function as signaling platforms. Large raft clusters are probably only assembled when protein modifications like phosphorylation increase the number of protein–protein interactions, leading to the coalescence of small clusters into larger domains on the scale of several hundred nanometers (8).
Figure 4.
Figure 4.
Lipid modifications of proteins as determinants of raft association. (A) Examples of lipid modification of proteins. Various lipid anchors play important roles in protein trafficking, membrane partitioning and proper function, likely mediated by their affinity for lipid rafts. The general paradigm is that anchoring by saturated fatty acids and sterols targets proteins to the more tightly packed environment of lipid rafts, whereas unsaturated and branched hydrocarbon chains tend to favor the less restrictive nonraft membranes. Palmitoylation of proteins can regulate raft partitioning. (A, Adapted from Levental et al. 2010a; reprinted with permission from the American Chemical Society © 2010.) (B) Quantification of raft protein abundance following removal of palmitoylated TM proteins by DTT or GPI-anchored proteins by GPI-specific phospholipase in GPMVs (average + SD from three independent experiments). (B, Adapted from Levental et al. 2010b; reprinted with permission from The National Academy of Sciences © 2010.)
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