GTPase-activating protein

In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.

G proteins can weakly hydrolyse GTP, breaking a phosphate bond to make GDP.

[5] This hydrolysis reaction, however, occurs very slowly, meaning G proteins have a built-in timer for their activity.

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.

Similarly, GAPs seem to induce a GDP-like charge distribution in the bound GTP.

[7] 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.

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.

[8] 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.

[10] 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.

Many GAPs have allosteric sites that serve as interfaces with downstream targets of the particular path that they regulate.

This positive regulatory binding of downstream targets to GAP serves as a negative feedback loop that eventually turns off the signaling that was originally activated.

There are also examples of negative regulatory mechanisms, where downstream targets of G protein signaling inhibit the GAPs.

[13] Under normal conditions, this signaling ultimately induces regulated cell growth and proliferation.

However, in the cancer state, such growth is no longer regulated and results in the formation of tumors.

In another case, expression of the Ras GAP is lost in several cancers due to improper epigenetic silencing of the gene.

T24 bladder cancer cells, for example, were shown to have a missense mutation, G12V, resulting in constitutively active Ras protein.

GAPs and their interaction with G proteins are, therefore, highly important clinically and are potential targets for cancer therapies.

G proteins have an inherent GTPase hydrolytic activity that is slow. However, in the presence of GAP, this hydrolytic activity is fast.
GAP works to open the G protein for nucleophilic attack by water and induce a GDP-like charge distribution.
Normally, G proteins are regulated by GAP, which results in controlled cell division.
Without GAP, G proteins are constitutively on because of their slow hydrolytic activity and GEFs constantly replacing GDP with GTP. This results in unregulated cell division and the formation of tumors.
G proteins without hydrolytic activity cannot hydrolyze bound GTP. GAPs cannot activate a nonfunctional enzyme, and the G protein is constitutively active, resulting in unregulated cell division and the formation of tumors.