FASEB Conference: Lipid Modifications of Proteins to be held on August 6-11, 2000 in Copper Mountain, CO

Federation Of Amer Societies For Exper Biology, Rockville MD

Investigators

Abstract

This project seeks partial support for the Federation of American Societies of Experimental Biology (FASEB) conference on "Lipid Modifications of Proteins" to be held from August 6 to August 11, 2000 at Copper Mountain, Colorado. This will be a state-of-the-art exploration of the structure and function of acylation, prenylation, and GPI-anchorage, the three major forms of lipid modification of proteins in eukaryotic cells, and will provide a unique opportunity for workers in these separate but related fields to exchange ideas and insights. Lipid modification of proteins is an extremely active field. The focus of research in this area has broadened in the past few years from an earlier focus on identification of lipid-modified proteins and structural studies, to include elucidation of the physiological role of the lipid group. Outlined below are the major themes of the meeting. Signaling. Surprisingly high proportions of lipid-linked proteins are key players in cellular signaling pathways. These include Ras, Src-family tyrosine kinases, heterotrimeric G proteins, and 7- transmembrane spanning hormone receptors. In virtually all cases, the lipid modifications are required for function. This focuses attention on the specific role of these lipid groups in cellular physiology. All lipid modifications can allow association of otherwise hydrophilic proteins with membranes. Why are there different lipid modifications? What do they have in common, and how do they differ? Recent results on Ras show that modification of the same protein with different lipids can substantially alter function. New insights into these and other questions can be best answered by discussion between people who focus on individual modifications. This is one of the most important goals of this meeting. Membrane rafts. An important function of both GPI anchorage and acylation is to target proteins to cholesterol and sphingolipid-rich membrane domains or rafts. The finding that a number of cellular signaling events occur in these domains is an exciting development of the past two years, and has attracted a great deal of interest. Structure and function of rafts, and function of lipid-linked proteins in them, is another theme of the conference. Related to this theme are the importance of cholesterol in the biogenesis and maintenance of membrane rafts and its recently discovered role as a post-translational modification of the cell surface signaling molecule, hedgehog. Therapeutic applications of inhibiting lipid modifications. A third theme of this meeting will explore how inhibition of lipid modification can be used as a highly effective strategy in fighting disease. This effort can be divided in two major subclasses. The first is the use of farnesyl transferase inhibitors to blunt the function of activated Ras. The second target is infectious disease caused by unicellular eukaryotic pathogens such as Trypanosoma, Leishmania, and Plasmodium. Most of these organisms express extremely high levels of GPI-anchored proteins. Synthesis of these complex structures by a multistep pathway requires a number of enzymes, some of which are specific to the pathogens and are not shared by mammalian hosts. These are key targets for drug design, an avenue that is being actively pursued. Pathogen-specific features of myristoylation and prenylation are being targeted similarly. Lipid modification and membrane targeting. All lipid modifications increase protein hydrophobicity, and all lipid modifications can target lipidated proteins to membranes. But how are lipidated proteins targeted to different membranes? The specificity of membrane targeting of acylated and prenylated proteins is one of the most active areas of current research. The emerging picture that acylated and prenylated proteins can follow complicated pathways through cells following synthesis will be explored. Lipid-modified proteins are integral players in the cellular processes of signal transduction, membrane and protein trafficking, cellular proliferation and differentiation. The disciplines of cell biology, genetics, biochemistry, and biophysics are all used to understand the biology of protein lipidation. This meeting provides the opportunity to integrate the information derived from these approaches into a more coherent picture of how lipid modifications contribute to protein function.