GTPase-activating Protein - Mechanism


The activity of G proteins comes from their ability to bind guanosine triphosphate (GTP). This molecule is the guanine base variant of the more familiar adenosine triphosphate (ATP). Binding of GTP inherently changes the activity of the G proteins through some kind of conformational change in the G proteins which makes them more active, such as the loss of inhibitory subunits. In their more active state, they can then bind other proteins and turn on downstream signaling targets more easily, but what is interesting about G proteins in regards to GAPs is that the G proteins have an inherent “off button”.

G proteins have a weak ability to hydrolyze GTP, breaking a phosphate bond to make GDP. In the GDP-bound state, the G proteins are subsequently “turned off”; in other words, they are inactivated and can no longer bind their targets. This hydrolysis reaction, however, occurs very slowly, so the G proteins in essence have a built-in timer for their activity. They have a window of activity followed by slow hydrolysis which turns them off. GAP works to accelerate this G protein timer because it increases the inherent hydrolytic GTPase activity of the G proteins, hence the name GTPase-activating protein.

More specifically, it appears 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 monophoshate, 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.

Read more about this topic:  GTPase-activating Protein

Famous quotes containing the word mechanism:

    The two elements the traveler first captures in the big city are extrahuman architecture and furious rhythm. Geometry and anguish. At first glance, the rhythm may be confused with gaiety, but when you look more closely at the mechanism of social life and the painful slavery of both men and machines, you see that it is nothing but a kind of typical, empty anguish that makes even crime and gangs forgivable means of escape.
    Federico García Lorca (1898–1936)

    When one of us dies of cancer, loses her mind, or commits suicide, we must not blame her for her inability to survive an ongoing political mechanism bent on the destruction of that human being. Sanity remains defined simply by the ability to cope with insane conditions.
    Ana Castillo (b. 1953)

    The law isn’t justice. It’s a very imperfect mechanism. If you press exactly the right buttons and are also lucky, justice may show up in the answer. A mechanism is all the law was ever intended to be.
    Raymond Chandler (1888–1959)