Meta-Biol

• Pathways

Rab GTPases are peripheral membrane proteins involved in membrane trafficking. Often through their indirect interactions with coat components, motors, tethering factors and SNAREs, the Rab GTPases serve as multifaceted organizers of almost all membrane trafficking processes in eukaryotic cells. To perform these diverse processes, Rab GTPases interconvert between an active GTP-bound form and an inactive, GDP-bound form. The GTP-bound activated form mediates membrane transport through specific interaction with multiple effector molecules (Zerial & McBride 2001, Stenmark 2009, Zhen & Stenmark 2015, Cherfils & Zeghouf 2013). Conversion from the GTP- to the GDP-bound form occurs through GTP hydrolysis, which is not only driven by the intrinsic GTPase activity of the Rab protein but is also catalysed by GTPase-activating proteins (GAPs). GAPs not only increase the rate of GTP hydrolysis, but they are also involved in the inactivation of RABs, making sure they are inactivated at the correct membrane. Human cells contain as many as 70 Rabs and at least 51 putative Rab GAPs (Pfeffer 2005). Only a few of these GAPs have been matched to a specific Rab substrate. The Tre-2/Bub2/Cdc16 (TBC) domain-containing RAB-specific GAPs (TBC/RABGAPs) are a key family of RAB regulators, where the TBC domain facilitates the inactivation of RABs by facilitating activation of GTPase activity of the RAB (Pan et al. 2006, Frasa et al. 2012, Stenmark 2009). Studies suggest that TBC/RABGAPs are more than just negative regulators of RABs and can integrate signalling between RABs and other small GTPases, thereby regulating numerous cellular processes like intracellular trafficking (Frasa et al. 2012).

The secretory membrane system allows a cell to regulate delivery of newly synthesized proteins, carbohydrates, and lipids to the cell surface, a necessity for growth and homeostasis. The system is made up of distinct organelles, including the endoplasmic reticulum (ER), Golgi complex, plasma membrane, and tubulovesicular transport intermediates. These organelles mediate intracellular membrane transport between themselves and the cell surface. Membrane traffic within this system flows along highly organized directional routes. Secretory cargo is synthesized and assembled in the ER and then transported to the Golgi complex for further processing and maturation. Upon arrival at the trans Golgi network (TGN), the cargo is sorted and packaged into post-Golgi carriers that move through the cytoplasm to fuse with the cell surface. This directional membrane flow is balanced by retrieval pathways that bring membrane and selected proteins back to the compartment of origin.

The transit of proteins and other cargo through the cell requires a cellular transport process in which transported substances are moved in membrane-bounded vesicles. Transported substances are enclosed in the vesicle lumen or located in the vesicle membrane. The transport process begins with the formation of the vesicle itself, often triggered by the interaction of the cargo with the vesicle formation machinery. Vesicular transport pathways can include vesicle formation, coating, budding, uncoating and target membrane fusion depending upon the function of the pathway described. Vesicle-mediated transport occurs from within cell via ER and Golgi transport, as well as functioning in the endocytosis of material taken into the cell via scavenger receptors.