TBC/RABGAPs (Homo sapiens)
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Description
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).
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TBC1D13 was identified as a specific GAP for Rab35 and observed to act as a potent inhibitor of insulin-stimulated GLUT4 translocation (Davey et al. 2012). TBC1D24 is a homolog of a Drosophila protein called skywalker, which has been shown to exhibit GAP activity towards Rab35 (Uytterhoeven et al. 2011).
TBC1 domain family member 2A (TBC1D2A also referred as ARMUS for variant c; PARIS1 for variant a) is a member of the TBC/RabGAP family (Tre2/Bub2/Cdc16; TBC domain) that specifically inactivates RAB7 by accelerating its GTPase activity. TBC1D2A binds specifically to activated Rac1 and its C-terminal TBC/RabGAP domain inactivates RAB7 to promote ARF6-induced E-Cadherin degradation (Frasa et al. 2010). During the regulation of autophagy, TBC1D2A is recruited to autophagosomes by interacting with LC3, a core autophagy regulator, thereby inhibiting RAB7 (Carroll et al. 2013)