RabGAPs

RabGAPs, or Rab GTPase-activating proteins, are a class of regulators that inactivate Rab family small GTPases by accelerating their GTP hydrolysis. Rab GTPases act as molecular switches in vesicular trafficking; when bound to GTP they recruit effectors that drive vesicle formation, movement, tethering, and fusion. RabGAPs promote the GDP-bound state, thereby terminating Rab activity and allowing cycles of recruitment and disassembly that coordinate trafficking events.

Most RabGAPs contain a catalytic RabGAP domain, often within a Tre-2/Bub2/Cdc16 (TBC) domain. In many organisms, the TBC domain is the defining feature and the largest RabGAP family is the TBC1D family in metazoans. Substrate specificity varies: individual RabGAPs can act on single Rab GTPases or on several members, and localization and additional regulatory regions help determine which Rab(s) they control.

RabGAPs are regulated by cellular signaling and subcellular localization. Phosphorylation by kinases such as Akt can modulate activity or localization, and interactions with adaptor proteins or 14-3-3 proteins can influence access to Rab substrates. They participate in virtually all membrane trafficking pathways, including endocytosis, recycling, Golgi–dissociation, exocytosis, endosome maturation, autophagy, and ciliogenesis, by shaping the activity cycles of the Rab GTPases that govern these steps.

Genetic and functional studies show that RabGAPs are evolutionarily conserved from yeast to humans and are essential for proper vesicle trafficking. Altered RabGAP function or regulation has been linked to diseases such as metabolic disorders, neurodevelopmental or neurodegenerative conditions, and ciliopathies, reflecting their central role in intracellular transport.