Why are lipid rafts not observed in vivo?

The existence of lipid rafts in live cells remains a topic of lively debate. Although large, micrometer-sized rafts are readily observed in artificial membranes, attempts to observe analogous domains in live cells place an upper limit of approximately 5 nm on their size. We suggest that integral membrane proteins attached to the cytoskeleton act as obstacles that limit the size of lipid domains. Computer simulations of a binary lipid mixture show that the presence of protein obstacles at only 5-10% by area dramatically reduces the tendency of the lipids to phase separate. These calculations emphasize the importance of spatial heterogeneity in cell membranes, which limits the transferability of conclusions drawn from artificial membranes to live cells.