Protein What? A Primer on Phosphorylation

What is protein phosphorylation?
Many proteins encoded by our genes are components of a vast communications network that functions inside cells, connecting them to their environments. This network is composed of signaling pathways that allow cells to respond to one another and to chemical messages from hormones and neurotransmitters. Protein phosphorylation is one of the main currencies used within cells to expedite this flow of information. In short, phosphorylation is the addition of a phosphate molecule to a protein. It’s been described as a sort of “on-off switch” for proteins and is often a critical step in determining what the cell machinery does next

How does it work?
Proteins inside cells are constantly interacting with enzymes and chemical messengers in a kind of molecular Pac Man game. In phosphorylation, a phosphate group is added to a protein, which often has the effect of transforming the protein’s shape, thereby changing the protein’s function. This regulates its activity and/or impacts how it interacts with other cellular components. These changes in turn, affect the “river of communication” causing “downstream” effects in the cell, such as opening or shutting certain gates and pumps in the cell’s outer membrane, modifying the expression of genes in the cell’s nucleus, or relaying signals to a group of other signaling proteins. The on-off switch endowed by protein phosphorylation is not complete without the reverse event – dephosphorylation, which occurs when a phosphate group is removed from a protein. This returns the protein to its pre-phosphorylation state. Hence, a protein can be activated or deactivated by the addition or deletion of a phosphate.

Who are the players?
Certain enzymes called protein kinases pick up a single phosphate molecule from a compound in the cell called ATP (adenosine triphosphate) and present it to a selected protein at a specific site along the protein’s chain of amino acids. Other enzymes, known as protein phosphatases, take away phosphate molecules from the protein, returning it to a dephosphorylated state. Either way, the protein’s shape and activity is fundamentally transformed. Kinases and phosphotases operate in continuous feedback loops and other regulatory networks to fine-tune the cell’s activity, like nature’s version of checks and balances.

What does it have to do with Parkinson’s?
In the subset of nerve cells that respond to dopamine, the phosphorylation of a protein called DARPP-32 is the central mechanism by which dopamine exerts its effects on neurons. DARPP-32 is more like a communications hub, able to be phosphorylated on multiple distinct sites in various combinations so that it transmits signals to a variety of pathways. The key to solving Parkinson’s disease may lie in the ability to “tweak” the balance of “on” vs. “off” settings for DARPP-32, thereby altering its signaling behavior to favor relief of Parkinsonian symptoms while discouraging pathways that may lead to unwanted side effects. By understanding the pathways through which dopamine associated kinases and phosphatases act on DARPP-32 and the pathways that DARPP-32 subsequently acts on, it should be possible to design pharmaceutical compounds that interact with either the kinases or phosphatases to potentiate or block their effects. In this way, the downstream effects that dopamine normally exerts on the cell could be enhanced, mimicked or tailored, even when little or no dopamine is available.