ArfGAP

ArfGAP, short for ARF GTPase-activating protein, refers to a family of regulatory proteins that stimulate the GTPase activity of ADP-ribosylation factor (ARF) small GTPases. By accelerating hydrolysis of GTP to GDP, ArfGAPs inactivate ARF proteins, enabling coat disassembly and progression of vesicle trafficking along the secretory and endocytic pathways. They are key regulators of membrane trafficking at the Golgi apparatus and endosomes, coordinating vesicle formation, cargo sorting, and vesicle uncoating.

Most ArfGAPs contain a catalytic ArfGAP domain, which includes a zinc-binding motif and an essential arginine finger that stabilizes the transition state during GTP hydrolysis. Many ArfGAPs also harbor additional domains or motifs that mediate interactions with membranes, lipids, or other proteins, such as PH domains, BAR domains, ankyrin repeats, or SH3 domains. These modules help determine subcellular localization and partnerships with coat components, adaptors, or cytoskeletal elements.

In humans, several ARFGAP genes encode classical ArfGAPs (for example ARFGAP1, ARFGAP2, ARFGAP3) and a broader set of ArfGAP-domain-containing proteins, including those with extra domains. Functional roles extend beyond coat remodeling to regulation of endocytic trafficking, actin cytoskeleton dynamics, and signaling cross-talk; some ArfGAPs have been implicated in ciliogenesis and neuronal development.

Dysregulation or mutation of ArfGAPs is associated with cellular defects and diseases, reflecting their broad importance in membrane trafficking and cellular organization.