The Origin of the Raft Hypothesis

Membrane heterogeneities resurfaced primarily as a necessity to explain a specific biological observation of preferential sorting of glycosphingolipids to apical membranes in polarized epithelial cells [4]. This idea was finally developed into a notion of lipid rafts by Simons and coworkers, and was centered on cholesterol-containing domains as the cornerstone of the raft model of life in a living cell membrane [5] (Fig. 3.2A).

Lipid rafts were hypothesized as specialized regions of cell membrane where sphingolipids and cholesterol come together as a result of chemical affinity and/or

Fluid Mosaik Modell

Fig. 3.1 The fluid-mosaic model of the plasma membrane. In this famous model, Singer and Nicholson summarized experi-

suggest that proteins are dissolved in a two-dimensional fluid. They also considered the possibility of small membrane domains

Fig. 3.1 The fluid-mosaic model of the plasma membrane. In this famous model, Singer and Nicholson summarized experi-

suggest that proteins are dissolved in a two-dimensional fluid. They also considered the possibility of small membrane domains mental observations from studying diffusion (~100 nm at most) in the fluid cell mem-processes in cell and artificial membranes to brane bilayer.

their preferential packing. These regions could include or exclude other lipids and proteins, and this specific segregation was proposed to mediate their biological function [5]. Lipid rafts have been implicated in a variety of functions such as sorting, endocytosis, signaling, and cell migration [6]. Although lipid rafts are implicated in many fundamental biological functions, there is significant confusion in their definition, evidence for their existence, and their precise role in biological function. Numerous models to explain their structure and function have been proposed and are summarized in Figure 3.2.

Lipid rafts have been studied and defined with a variety of techniques, and this has resulted in various terminologies such as 'microdomains', detergent-insoluble glycolipid/glycosphingolipid-enriched complexes/membranes (DIGs), and detergent-resistant membranes (DRMs). In order to avoid confusion, the term "lipid rafts" in this chapter will be used henceforth as a general description of lipid-based membrane heterogeneity, and wherever necessary followed by the method used to define it.

This chapter focuses on the biophysical tools that have been used to examine membrane heterogeneities.

Lipid Rafts Sphingolipids

Fig. 3.2 Current raft models. (A) The most commonly cited hypothesis for membrane rafts proposed by K. Simons (Dresden, Germany) [5] depicts rafts that are relatively large structures (~50 nm), enriched in cholesterol and sphingolipid (SL), with which proteins are likely to associate. (B) Anderson and Jacobson visualize rafts as lipid shells which are small, dynamic molecular-scale assemblies in which "raft" proteins preferentially associate with certain types of lipids [83]. The recruitment of these "shells" into functional structures could be a dynamic and regulated process. (C) Another point of view is that a large fraction of the cell membrane is raft-like and exists as a "mosaic of domains"; cells regulate the amount of the different types of domains via a cholesterol-based mechanism [84]. (D) Actively generated spatial and temporal organization of raft components. A different picture that is consistent with data from GPI-anchored protein studies in living cells suggest that pre-existing lipid assemblies are small and dynamic, and coexist with monomers [30]. They are actively induced to form large-scale stable "rafts". Black circles = GPI-anchored proteins; red and pink circles = non-raft-associated lipids; yellow circles = raft-associated lipids; green = cholesterol. Scale bar = ~5 nm. (Reprinted with permission from [30].)

48 3 The Biophysical Characterization of Lipid Rafts GPI-anchored protein

Lipid Raft Hypothesis
Fig. 3.3 (A) Membrane topology of GPI-anchored proteins in comparison to transmembrane (TM) proteins and fatty-acid linked proteins. (B) Core residues of the GPI-anchor. (Reprinted with permission from [7].)
Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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