This week we move on to proteins and enzymes, which means time spent with some of my favorite enzymes, protein kinases. Proteins kinases are enzymes that attach phosphate groups to other proteins. Considering the size of a typical protein, this addition of a few atoms (one phosphorous and three oxygens) does not seem like a big deal. Sort of like the little sprig of mint dressing an amazing entree at a nice restaurant. But that is not the case.. the addition of a little phosphate can have drastic consequences on the structure, and consequently, the function, of a protein molecule. An enzyme modified by a phosphorylation event may change one hundredfold or more in its activity, upward or downward, depending on what the phosphate does to the shape of the protein. The power of the phosphate resides in that one little negative charge that it carries. A few extra electrons strategically placed can change everything.
Many, many proteins are regulated by phosphorylation. Not only can the activity be affected, but also the stability, localization, substrate specificity and more. And it is not uncommon for one protein kinase to have its activity regulated by another protein kinase, which in turn is regulated by yet another protein kinase, and so on and so on and so on.
The phosphate groups are removed by opposing enzymes called protein phosphatases. We do not know nearly as much about these enzymes. I heard a fascinating seminar about an attempt to design protein phosphatase inhibitors, including inhibitors for my all time favorite phosphatase (Cdc25A – long story). There is some promise that these inhibitors might help treat a host of problems, from cardiovascular disease to cancer.
When one spends too much time thinking about kinases, phosphatases and phosphate groups, one sometimes develops the mindset that phosphorylation rules the world, or at least, rules the cell, from which all living systems are made.
Phosphorylation is a very digital event. A given amino acid in a protein is either phosphorylated or it is not. The phosphate confers a single negative charge. The subtleties and gradations arise as they might in any digital system. In a given protein, there may be multiple phosphorylation sites, some of which are occupied and some which are not in any given condition. This allows for an enzymes to be active to varying degree rather than just “on” or “off”. Or in a population of many enzyme molecules, not all may be phosphorylated at a specific site if the kinase activity is low. There are stochastic elements to be sure.
I realize this is an incredibly reductionist view and one about which I am not particularly proud, but if I can convince myself that digital devices are not scarier than the cells I know and love, then maybe I won’t be so afraid of that other cell in my life – the one called iPhone that my 8 year old daughter has to teach me how to operate.