GAPs

GAPs, short for GTPase-activating proteins, are a diverse family of regulatory proteins that inactivate small GTPases, molecular switches that control a wide range of cellular processes. By accelerating the hydrolysis of GTP to GDP, GAPs switch GTPases from an active to an inactive state, helping to turn off signaling pathways that govern cell growth, differentiation, cytoskeleton dynamics, vesicle trafficking, and gene expression.

Most GAPs contain a catalytic GAP domain that interacts with a target GTPase. A hallmark of many Ras-family GAPs is the insertion of a catalytic residue, often described as an arginine finger, that stabilizes the transition state of GTP hydrolysis. GAPs are classified according to their target GTPases: RasGAPs regulate Ras and related small GTPases; RhoGAPs regulate the Rho family involved in actin dynamics; and RabGAPs regulate Rab family members essential for vesicle trafficking. Notable examples include NF1, a RasGAP that regulates Ras signaling and is associated with neurofibromatosis type 1, and p120GAP (RASA1), another RasGAP. In the Rho family, p190RhoGAP and other ARHGAP proteins modulate cytoskeletal organization.

GAP activity is tightly regulated by cellular context, including subcellular localization, phosphorylation, and interactions with receptors or adaptor proteins. GAPs oppose the actions of GEFs, which activate GTPases by promoting GDP-to-GTP exchange. Dysregulation or mutation of GAPs has been linked to cancers and developmental disorders, reflecting their central role in controlling signaling networks.