Better Late Than Never: A Role for Rabs Late in Exocytosis

suggesting that they too may perform a common function and yet confer specificity to each trafficking step. * Department of Neurobiology and Anatomy Genetic analysis of the yeast constitutive secretory University of Texas pathway has converged with progress on synaptic pro-Health Science Center teins, and mammalian homologs of most of the essential Houston, Texas 77030 yeast secretory proteins, including rabs, have been iden-† Howard Hughes Medical Institute tified (Hay and Scheller, 1997). Biochemical studies and Department of Molecular and Cellular Physiology in vitro reconstitution of transport steps have indicated Stanford University a requirement for the rab proteins but have yet to provide Stanford, California 94305 a clear common function. The function of the rab proteins is likely dependent on their enzyme activity as well Since the discovery of the rab family of small GTP-as their effectors. Much has been learned about the binding proteins in yeast screens for vesicle trafficking possible function of the rab GTPase activity and the mutants, a search has been underway for a precise proteins involved in the rab GDP-GTP cycle from studies definition of their role in the secretory pathway. The rab on many different rab proteins, with the assumption that this activity and its function are common to all rabs proteins comprise a homologous, large (‫04ف‬ mamma-(Sudhof, 1997; Novick and Zerial, 1997). The cycling of lian proteins, 11 in yeast) branch of the ras superfamily rab proteins from the GDP-bound state to the GTP-whose members are present at all trafficking steps bound state appears to correspond with association of throughout the secretory pathway (Novick and Zerial, the rab proteins with their target organelles. The search 1997). Some rab proteins are differentially expressed for rab effectors has proven somewhat more elusive, and may therefore have specific roles in certain cell and although many new proteins have recently been types. Rab3a and its isoform, rab3c, are expressed ex-discovered as rab-binding proteins using the two-hybrid clusively in neurons and neuroendocrine cells and have approach, they lack a common structure that would therefore garnered considerable interest because of allow coherent speculation about a common function. their possible role in regulated secretion. In the past Rabphilin 3a was the first identified rab effector (Novick few years, our insight into the molecular mechanisms and Zerial, 1997). Rabphilin 3a is a GTP-dependent of exocytosis has increased, although it has remained rab3a-binding protein associated with the synaptic vesi-difficult to place rab3a in …