GTPaseactivating

GTPase-activating refers to the function of GTPase-activating proteins (GAPs), which stimulate the intrinsic GTPase activity of small GTP-binding proteins and thereby promote their inactivation. Small GTPases act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, governing processes such as cell growth, cytoskeletal dynamics, and vesicle trafficking. GAPs accelerate the hydrolysis of GTP to GDP much faster than the enzyme’s baseline rate, effectively turning signaling pathways off.

Mechanistically, GAPs usually interact with their target GTPase at the active site to stabilize the transition state of GTP hydrolysis. Many Ras-family GAPs contribute an arginine finger that helps orient catalytic water and stabilize the transition state; some GTPases rely on GAPs for efficient catalysis while the intrinsic GTPase activity remains essential. In many systems, the GTPase itself provides key residues (such as a catalytic glutamine) that work in concert with the GAP.

GAPs are diverse and typically exhibit specificity for particular families or members of GTPases. Examples include Ras-GAPs (such as NF1 and p120GAP/RASA1), which regulate Ras signaling; RhoGAPs that modulate Rho family GTPases involved in the actin cytoskeleton; and RabGAPs and RanGAPs that control vesicle trafficking and nucleocytoplasmic transport, respectively. A subset of GAPs contains additional domains that regulate localization and interactions, reflecting integration into broader signaling networks.

Regulation of GAP activity occurs through phosphorylation, interactions with adaptor proteins, and subcellular localization, ensuring that GTPase cycling is coordinated with cellular context. Dysregulation of GAPs can contribute to disease, including cancer and developmental disorders, by altering signaling thresholds and timing. GAPs function in balance with GTP exchange factors (GEFs), which promote GDP-to-GTP activation, together controlling GTPase signaling dynamics.