Arf Proteins and Their Regulators: At the Interface Between Membrane Lipids and the Protein Trafficking Machinery

The Arf small GTP-binding (G) proteins regulate membrane traffic and organelle structure in eukaryotic cells through a regulated cycle of GTP binding and hydrolysis. The first function identified for Arf proteins was recruitment of cytosolic coat complexes to membranes to mediate vesicle formation. However, subsequent studies have uncovered additional functions, including roles in plasma membrane signalling pathways, cytoskeleton regulation, lipid droplet function, and non-vesicular lipid transport. In contrast to other families of G proteins, there are only a few Arf proteins in each organism, yet they function specifically at many different cellular locations. Part of this specificity is achieved by formation of complexes with their guanine nucleotide-exchange factors (GEFs) and GTPase activating proteins (GAPs) that catalyse GTP binding and hydrolysis, respectively. Because these regulators outnumber their Arf substrates by at least 3-to-1, an important aspect of understanding Arf function is elucidating the mechanisms by which a single Arf protein is incorporated into different GEF, GAP, and effector complexes. New insights into these mechanisms have come from recent studies showing GEF–effector interactions, Arf activation cascades, and positive feedback loops. A unifying theme in the function of Arf proteins, carried out in conjunction with their regulators and effectors, is sensing and modulating the properties of the lipids that make up cellular membranes.