Rab GEFs and GAPs: The enigma variations

© 2014 Springer International Publishing Switzerland. All rights reserved. Rab GTPases are key regulators of membrane traffic activated on the surface of organelle and vesicle membranes during vesicle trafficking events, cell polarisation and autophagy. Rabs undergo a cycle of activation involving GTP binding and inactivation involving GTP hydrolysis in response to cellular regulators. Each Rab has a cognate GDP-GTP exchange factor (GEF) promoting release of GDP and subsequent binding of GTP, and a GTPase activating protein (GAP) stimulating the slow intrinsic GTP hydrolysis. Together these GEF and GAP regulators determine when and where a specific Rab is activated, and how long its activity will persist. Rab GEFs fall into a number of discrete families, the largest of which are the Vps9 domain, DENN and DENN domain-related proteins. Other Rab GEF families, including TRAPP, Ric1-Rgp1, Mon1-Ccz1 and Hps1-Hps4, are comprised of two or more polypeptide chains. By contrast, almost all known Rab GAPs possess a TBC1 domain. Here I will discuss the mechanisms by which these GEFs and GAPs regulate Rab GTPases, highlighting common themes and points of difference, and briefly outlining the cellular processes they regulate.