GTPase-activating protein

GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP’s role in this function is to turn the G protein’s activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.

GAP are heavily linked to the G-protein linked receptor family. The activity of G proteins comes from their ability to bind guanosine triphosphate (GTP). Binding of GTP inherently changes the activity of the G proteins and increases their activity, through the loss of inhibitory subunits. In this more active state, G proteins can bind other proteins and turn on downstream signalling targets. This whole process is regulated by GAPs, which can down regulate the activity of G proteins.

G proteins can weakly hydrolyse GTP, breaking a phosphate bond to make GDP. In the GDP-bound state, the G proteins are subsequently inactivated and can no longer bind their targets. This hydrolysis reaction, however, occurs very slowly, meaning G proteins have a built-in timer for their activity. G proteins have a window of activity followed by slow hydrolysis, which turns them off. GAP accelerates this G protein timer by increasing the hydrolytic GTPase activity of the G proteins, hence the name GTPase-activating protein.

It is thought that GAPs serve to make GTP on the G protein a better substrate for nucleophilic attack and lower the transition state energy for the hydrolysis reaction. For example, many GAPs of the small G proteins have a conserved finger-like domain, usually an arginine finger, which changes the conformation of the GTP-bound G protein to orient the GTP for better nucleophilic attack by water. This makes the GTP a better substrate for the reaction. Similarly, GAPs seem to induce a GDP-like charge distribution in the bound GTP. Because the change in charge distribution makes the GTP substrate more like the products of the reaction, GDP and monophosphate, this, along with opening the molecule for nucleophilic attack, lowers the transition state energy barrier of the reaction and allows GTP to be hydrolyzed more readily. GAPs, then, work to enhance the GTP hydrolysis reaction of the G proteins. By doing so, they accelerate the G protein's built-in timer, which inactivates the G proteins more quickly, and along with the inactivation of GEFs, this keeps the G protein signal off. GAPs, then, are critical in the regulation of G proteins.

...
Wikipedia