Model of E-selectin distribution in membrane domains of endothelial cells. E-selectin distributes reversibly among nonraft and raft domains in the plasma membrane of endothelial cells. At any time point, most E-selectin molecules are in nonraft domains, and some of these are clustered in clathrin-coated pits. A minor population of E-selectin clusters in lipid rafts that appear to be distinct from caveolae. The major pathway for internalization of E-selectin is through clathrin-coated pits. Hypertonic medium prevents clustering of E-selectin in clathrin-coated pits by disrupting the clathrin lattice structure. MβCD prevents clustering of E-selectin in lipid rafts by chelating cholesterol, a major component of the rafts. Disruption of both structures on endothelial cells markedly impairs the ability of E-selectin to mediate leukocyte rolling under flow, probably by hindering the ability of E-selectin to form clusters of bonds with ligands on rolling leukocytes.