Synthesis of functional Ras lipoproteins and fluorescent derivatives

For the study of biological signal transduction, access to correctly lipida ted proteins is of utmost importance. Furthermore, access to bioconjugates that embody the correct structure of the protein but that may additionally carry different lipid groups or labels (i.e., fluorescent tags) by which th e protein can be traced in biological systems, could provide invaluable rea gents. We report here of the development of techniques for the synthesis of a series of modified Ras proteins. These modified Ras proteins carry a num ber of different, natural and non-natural lipid residues, and the process w as extended to also provide access to a number of fluorescently labeled der ivatives. The maleimide group provided the key to link chemically synthesiz ed lipopeptide molecules in a specific and efficient manner to a truncated form of the H-Ras protein. Furthermore, a preliminary study on the biologic al activity of the natural Rns protein derivative (containing the normal fa rnesyl and palmitoyl lipid residues) has shown full biological activity. Th is result highlights the usefulness of these compounds as invaluable tools for the study of Ras signal transduction processes and the plasma membrane localization of the Ras proteins.