The lipid bilayer is a two-dimensional fluid, where lipid molecules exchange slowly between leaflets but are mobile within the leaflet. This mobility consists of two parts:
• the "translational freedom" of a molecule - that is, its lateral mobility; and
• the "configurational freedom" that is, the ability to flex parts of the molecule and to rotate bonds in its carbon backbone.
Synthetic bilayers change from a liquid state with high translational and configurational freedom into a rigid gel state at a characteristic freezing point. Cell membranes at physiological temperatures are almost always in the liquid state, but can contain regions with high configurational order, as will be described later. Importantly, the lipid bilayer of cell membranes is asymmetric, with a different lipid composition in the two leaflets. The main lipid components of cellular membranes are glycerophospholipids, with the most abundant species being phosphatidylcholine (PC) in the exoplasmic leaflet and phosphatidylethanolamine (PE) and phos-phatidylserine (PS) in the inner leaflet, as well as sphingolipids with glycosphingo-lipids and sphingomyelin (SM) mostly localized to the exoplasmic leaflet. Sterols make up the third lipid class, and are present in both leaflets. Mammalian cell membranes contain only one sterol, namely cholesterol, but probably more than thousand different glyco- and sphingolipid species, emerging from the combinatorial propensity to assemble lipids from different backbones linked in different ways with two varying hydrocarbon chains and a vast number of headgroups. A large number of flippases and translocators tightly control the asymmetric distribution of all these lipids across the bilayer .
Lipids are differentially distributed between cellular organelles. The endoplasmic reticulum and the Golgi-complex contain mainly glycerophospholipids and only small amounts of sphingolipids, whereas the plasma membrane is relatively enriched in SM and glycosphingolipids . Also within the membrane plane of one organelle, lipids are believed to be heterogeneously arranged. Caveolae - small invaginations of the plasma membrane - are enriched in glycosphingolipids , and phosphatidylinositol-3'-phosphate (PI(3)P) is concentrated in subdomains of early endosome membranes . Recently, vacuole-fusion in yeast has been shown to be controlled by microdomains of ergosterol, diacylglycerol and phosphoinosi-tide-3-and-4-phosphate . Furthermore, membranes are differentially susceptible to extraction by detergents such as Triton X-100 or CHAPS at 4 °C, with some proteins and lipids being completely solubilized and others forming so-called "detergent-resistant membranes" (DRM; for a review, see ). These findings suggested that cell membranes contained microdomains in which lipids were more tightly packed and thus not accessible to the detergent, although it is widely accepted that DRMs do not have an exact in-vivo correlate but are defined by being formed during the detergent treatment . These microdomains were later termed "rafts" and were described as sphingolipid-cholesterol assemblies containing a subset of membrane proteins . Currently, the raft hypothesis is heavily debated [12-14], with the main discussion points being the methodologies to study rafts and the size of the domains (see below). The core of the raft concept is that cell membranes phase-separate into different domains and that this is a lipid-driven process. In light of the ongoing discussion in the field, the following sections will provide an overview about what is known about phase separation, first discussing the studies conducted in model membrane systems and later in cell membranes.
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