ArfGAPs

ArfGAPs, or ADP‑ribosylation factor GTPase‑activating proteins, regulate the activity of the Arf family of small GTPases. They accelerate GTP hydrolysis on Arf, switching it from an active GTP‑bound state to an inactive GDP‑bound state, thereby controlling the assembly of coat protein complexes that drive vesicle budding and trafficking within eukaryotic cells.

Most ArfGAPs contain a conserved ArfGAP domain at their C‑terminus, which coordinates a zinc ion and forms the catalytic pocket necessary for GTPase activation. Additional domains, such as BAR or PH domains, are frequently present and mediate membrane association or protein‑protein interactions. The N‑terminal regions can include regulatory motifs, allowing integration of signals from kinases and phosphoinositides.

Functionally, ArfGAPs participate in several trafficking pathways. They are essential for COPI vesicle formation at the Golgi, for clathrin-mediated endocytosis at the plasma membrane, and for the maturation of endosomes. Some members also influence actin dynamics and membrane curvature, linking vesicle formation to cytoskeletal remodeling.

Representative members include the ASAP1 and AGAP family in mammals, Sec7‑like ArfGAPs in yeast (e.g., Tsg101), and Drosophila ArfGAP5. The diversity of family members reflects specialization: for example, the five human ArfGAP1 isoforms differ in subcellular localization and regulatory interactions.

Altered ArfGAP activity is implicated in human disease. Mutations in the ArfGAP1 gene are associated with neurodevelopmental disorders, while dysregulation of ASAP1 contributes to cancer metastasis. Consequently, the ArfGAP domain is an attractive target for small‑molecule modulators aimed at correcting trafficking defects or inhibiting pathological signaling.