Rab GEFs and GAPs: The Enigma Variations - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 79

Chapter 5
Rab GEFs and GAPs: The Enigma
Variations
Francis A. Barr
Abstract 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 regula-
tors. 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.
Keywords Vesicle traffic • Rab GTPase • GEF • GAP • TBC1 domain • Longin
domain
5.1 Rab Function and the Need for Regulation
Rab GTPases form a large and highly conserved subfamily of the Ras-related GTPase
in eukaryotic cells. Rabs are key regulators of membrane traffic activated at the
surface of organelle and vesicle membranes during vesicle trafficking events, cell
polarisation and autophagy (Zerial and McBride 2001 ; Pfeffer and Aivazian 2004 ).