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Revitalizing membrane rafts:
new tools and insights

Kai Simons and Mathias J. Gerl

Abstract | Ten years ago, we wrote a Review on lipid rafts and signalling in the launch issue of Nature Reviews MolecularCell Biology. At the time, this field was suffering from ambiguous methodology and imprecise nomenclature. Now, new techniques are deepening our insight into the dynamics of membrane organization. Here, we discuss how the field has matured and present an evolving model in which membranes are occupied by fluctuating nanoscale assemblies of sphingolipids, cholesterol and proteins that can bestabilized into platforms that are important in signalling, viral infection and membrane trafficking.

A 50–80‑nm, flask‑shaped pit that forms in the plasma membrane and is enriched in caveolins, cavins, sphingolipids and cholesterol.

Max Planck Institute of Cell Biology and Genetics, Pfotenhauerstraβe 108,01307 Dresden, Germany.
Cell membranes contain hundreds of lipids in two asym- metric leaflets1 and a plethora of proteins. For several decades, membrane research was dominated by the idea that proteins were the key factors for membrane functionality, whereas lipids were regarded as a passive, fluidsolvent2. Introducing the lipid raft concept in 1997, we postulated that sphingolipid–cholesterol–protein assemblies could function in membrane trafficking and signalling3. These assemblies, or rafts, were thought to be characterized by their tight lipid packing, similar to the sterol-dependent, liquid-ordered phase in model membranes. The novelty of the raft concept was that it brought lipids back intothe picture by giving them a function and by introducing chemical specificity into the lateral heterogeneity of membranes.
When we wrote our first Review in this journal4, the emerging raft field had become increasingly confused by ambiguous methodology and imprecise nomencla-
ture. Caveolae, for example, became synonymous with
rafts but clearly represented only a subset of membraneassemblies defined by the action of the protein caveo- lin5. Complicating matters further was the size of the sphingolipid–cholesterol–protein assemblies being studied, which were below the resolution of light micro- scopy. Only after cross-linking did raft proteins and lipid constituents cluster together to form micrometre-size, quilt-like patches.
Our focus in the first Review was to emphasize thatrafts are small and dynamic and can be stabilized to form larger microdomains that function in membrane trafficking and signalling. We proposed that three types of assembly should be recognized in cell mem- branes — rafts, clustered rafts and caveolae (a subset of clustered rafts) — and that the residue remaining insoluble after detergent extraction should be called
detergent-resistant membrane(DRM) fractions. We also summarized the tools that were available for defin- ing rafts and discussed their strengths and shortcom- ings. Obviously, what was known about lipid rafts and membrane organization at the time was dependent on the available methodology.
The rationale of the present Review is to summa- rize where we stand today and to highlight the impor- tant role that new technologyhas had in moving the
field forwards (BOX 1). We describe how membrane
rafts are now defined as dynamic, nanoscale, sterol–
sphingolipid-enriched, ordered assemblies of proteins and lipids, in which the metastable raft resting state can be stimulated to coalesce into larger, more stable raft domains by specific lipid–lipid, protein–lipid and protein–protein oligomerizing interactions (FIG....