Shedding a light
on cellular switching
News and Views, september 2011
Most of the time, we don't even think about it: switching on the light. Only half awake, our hand can find the button on the wall and push it. And there you go, the light is turned on. In our cells, some proteins can also be switched on and off. Not with a button of course, but by adding or removing energy in the form of a small molecule, ATP. In this way, cells control when these proteins are active or not.
One of the proteins involved in the repair of mismatches in our DNA, the protein MutS, can also be switched on. It is remarkable how well this molecular switch can be compared to the electrical switch in our homes. When we push the light button, we physically close the electrical circuit in the switch, allowing power to flow to the light bulb. And when we push the button again, the electrical circuit is broken and the light is turned off. In mismatch repair, ATP is the button. If ATP binds to MutS, it will change the shape of the protein in such a way that it can now recruit the next protein partner in the DNA repair pathway. In this way, MutS is switched on by ATP.
What in the cell is the equivalent of our hand touching the light button? What is the signal that determines whether the button has to be switched? It has long been known that this is the DNA mismatch. When the MutS protein encounters a mismatch it can tightly bind to this DNA. Only when MutS is bound to a DNA mismatch it can be switched on by ATP. When the ATP is split, the switch is reset leaving MutS inactive again.
By comparing the switching of MutS to that of another group of proteins, the 'mismatch2model' consortium has now discovered that ATP is not working alone. The consortium has identified magnesium as an important element of the trigger. You might know magnesium as the white powder used by athletes, such as gymnasts and weight lifters, to improve their grip on the apparatus or lifting bar. In that case, magnesium (Mg) is in a compound together with carbonate (chalk). In the cell, magnesium floats freely as a positively charged ion (Mg2+) and often interacts with the negatively charged ATP molecule to form the Mg.ATP. In fact, this is the form of ATP that is binding tightly to MutS.
If the magnesium ion is absent, or if MutS cannot properly recognize the magnesium, the switch does not function optimally. The ATP is still bound,
but not as tight, and the change in shape of MutS occurs much more slowly than with Mg.ATP. This slows down the whole mismatch repair process.
So, while ATP is still the trigger that switches on MutS, the speed at which this occurs is controlled by magnesium. The identification of magnesium as the controller of the switch in MutS is important to come to a full understanding of all details of the mismatch repair pathway. Only then researchers will be able to draw up a good model of this complicated process. Fortunately, switching on the lights does not challenge our brain to the same extent as this kind of research. That would be hard, only half awake in the morning.
