Molecular Dynamics and Interactions for Creation of Stimulation‐Induced Stabilized Rafts from Small Unstable Steady‐State Rafts

Abstract

We have evaluated the sizes and lifetimes of rafts in the plasma membrane from the existing literature, with a special attention paid to their intrinsically broad distributions and the limited time and space scales that are covered by the observation methods used for these studies. Distinguishing the rafts in the steady state (reserve rafts) from those after stimulation or unintentional crosslinking of raft molecules (stabilized receptorcluster rafts) is critically important. In resting cells, the rafts appear small and unstable, and the consensus now is that their sizes are smaller than the optical diffraction limit (250 nm). Upon stimulation, the raft-preferring receptors are clustered, inducing larger, stabilized rafts, probably by coalescing small, unstable rafts or cholesterolglycosphingolipid complexes in the receptor clusters. This receptor-cluster-induced conversion of raft types may be caused by suppression of alkyl chain isomerization and the lipid lateral diffusion in the cluster, with the aid of exclusion of cholesterol from the bulk domain and the boundary region of the majority of transmembrane proteins. We critically inspected the possible analogy to the boundary lipid concept. Finally, we propose a hypothesis for the coupling of GPI-anchored receptor signals with lipid-anchored signaling molecules in the inner-leaflet raft.

Thermotropic Phase Transition in Soluble Nanoscale Lipid Bilayers

“…Similar sizes for pure lipid domains in biological membranes have been obtained from simple estimates based on the protein/lipid ratio 2,25 . Such small domains have also been detected experimentally [26][27][28][29] . These findings suggest that up to half of all lipids may be in contact with protein and, by definition, belong to the boundary lipid layers.…”

Lipid rafts: contentious only from simplistic standpoints

“…Single-particle tracking experiments at high temporal and moderate spatial resolution also indicate that single GPI-anchored proteins are associated with very small (<10 nm) domains with short lifetimes (<0.1 ms), although the size and stability of these domains increase if GPIanchored proteins are crosslinked 26 . Moreover, the results of earlier FRET and electron paramagnetic resonance (EPR)-spin labelling experiments can only be rationalized if rafts are small and unstable, or raft proteins exchange rapidly with non-raft membrane on a timescale of <0.1 ms (REFS 27,28 ).…”

“…• Kusumi and colleagues have shown that the plasma membrane is compartmentalized by a picket fence of transmembrane proteins that are anchored to the submembrane actin cytoskeleton 26,[67][68][69] . The fence allows relative free lateral diffusion of lipids within compartments but restricts movement between compartments.…”

“…• Cholesterol is excluded from the immediate vicinity of transmembrane proteins; therefore the local concentration of cholesterol will vary on a nanometer-length scale 26,70 .…”

Lipid rafts, cholesterol, and the brain

“…This indicates that the fraction of proteins associated with domains is constant over a wide range of expression levels, a result that implies these domains are actively regulated by the cell. The possibility that protein-protein or protein-lipid interactions stabilize small transient domains and/or induce the formation of larger, longer-lived entities has been proposed by a number of groups (Kusumi et al 2004;Kusumi and Suzuki 2005;Hancock 2006;Jacobson et al 2007). Finally, the possibility that cell membranes exist close to a phase boundary and thus small changes in lipid composition could drive raft assembly or disassembly has also been suggested (Keller et al 2004;Veatch and Keller 2005).…”