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. 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. In general, GAPs tend to be pretty specific for their target G proteins. The exact mechanism of target specificity is not fully known, but it is likely that this specificity comes from a variety of factors. At the most basic level, GAP-to-G protein specificity may come simply from the timing and location of protein expression. RGS9-1, for example, is specifically expressed in the rod and cone photoreceptors in the eye retina, and is the only one to interact with G proteins involved in phototransduction in this area. A certain GAP and a certain G protein happen to be expressed in the same time and place, and that is how the cell ensures specificity. Meanwhile, scaffold proteins can also sequester the proper GAP to its G protein and enhance the proper binding interactions. These binding interactions may be specific for a particular GAP and G protein. Also, GAPs may have particular amino acid domains that recognize only a particular G protein. Binding to other G proteins may not have the same favorable interactions, and they therefore do not interact. GAPs can, therefore, regulate specific G proteins. EIF5 is a GTPase-activating protein. Furthermore, YopE is a protein domain that is a Rho GTPase-activating protein (GAP), which targets small GTPases such as RhoA, Rac1, and Rac2. The GAPs that act on small GTP-binding proteins of the Ras superfamily have conserved structures and use similar mechanisms, An example of a GTPase is the monomer Ran, which is found in the cytosol as well as the nucleus. Hydrolysis of GTP by Ran is thought to provide the energy needed to transport nuclear proteins into the cell. Ran is turned on and off by GEFs and GAPs, respectively. Most GAPs that act on alpha subunits of heterotrimeric G proteins belong to a distinct family, the RGS protein family.