Different microdomains contain K-ras and H-ras.

By combining high-resolution electron microscopy and sophisticated statistical analysis, Prior et al. (page 165) have developed a powerful new technique for studying lipid microdomains, and used it to examine the localization of Ras proteins in the plasma membrane. Since low imaging resolution is a major obstacle to studying microdomains, the authors used electron microscopy to look at sheets of plasma membrane ripped from intact cells. Specific proteins were labeled with gold particles, and each labeled spot on the membrane was numbered and related to every other spot to detect nonrandom distribution patterns. Though the initial focus was on Ras, the technique should be applicable to virtually any membrane-associated protein.

H-ras and K-ras appear to localize to distinct microdomains on the inner leaflet of the plasma membrane, which may help explain how these highly homologous proteins send different signals. To localize correctly, K-ras requires its farnesyl moiety, and H-ras requires the galectin-1 protein. Inner leaflet lipid raft domains, with an average estimated 40-nm diameter, were only loosely associated with the lipid rafts on the outer leaflet of the membrane, suggesting that the strength of the linkage between inner and outer leaflet rafts could be a novel control point for signal transduction. ▪