SNARE proteins and ‘membrane rafts’

The original ‘lipid raft’ hypothesis proposed that lipid‐platforms/rafts form in the exoplasmic plasmalemmal leaflet by tight clustering of sphingolipids and cholesterol. Their physical state, presumably similar to liquid‐ordered phases in model membranes, would confer detergent resistance to rafts and enriched proteins therein. Based on this concept, detergent resistant membranes (DRMs) from solubilized cells were considered to reflect pre‐existing ‘lipid rafts’ in live cells. To date, more than 200 proteins were found in DRMs including also members of the SNARE superfamily, which are small membrane proteins involved in intracellular fusion steps. Their raft association indicates that they are not uniformly distributed, and, indeed, microscopic studies revealed that SNAREs concentrate in submicrometre‐sized, cholesterol‐dependent clusters at which vesicles fuse. However, the idea that SNARE clusters are ‘lipid rafts’ was challenged, as they do not colocalize with raft markers, and SNAREs are excluded from liquid‐ordered phases in model membranes. Independent from this disagreement, in recent years the solubilization criterion has been criticized for several reasons, calling for a more exact definition of rafts. At a recent consensus on a revised raft model, the term ‘lipid rafts’ was replaced by ‘membrane rafts’ that were defined as ‘small (10–200 nm), heterogeneous, highly dynamic, sterol‐ and sphingolipid‐enriched domains that compartmentalize cellular processes’. As a result, after dismissing the terms ‘detergent resistant’ and ‘liquid‐ordered’, it now appears that SNARE clusters are bona fide ‘membrane rafts’.