Overview

The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.

During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly phosphorylated amino acids. Accordingly, protein kinases are classified as serine/threonine kinases, tyrosine kinases, or dual action kinases if they can phosphorylate all three amino acids. Conversely, protein phosphatases catalyze the removal of the phosphate group (dephosphorylation), restoring the original properties of the protein.

Under physiological conditions, phosphorylation and dephosphorylation are tightly regulated to prevent prolonged changes in protein structure and function. Disruption of this balance can cause diseases, including cancer and various neurodegenerative disorders. For instance, a protein called tau is hyperphosphorylated in Alzheimer’s disease (AD). Physiologically, tau regulates the shape, structure, and development of neurons. The tau protein contains over 80 serine, threonine, and tyrosine residues, of which only a fraction is usually phosphorylated. In the brains of patients with AD, tau is abnormally and excessively phosphorylated. This alters the solubility of the protein, forming toxic insoluble aggregates that lead to neuronal death.

Procedure

Phosphorylation, the addition of a phosphate group, is an important chemical modification that helps cells to regulate protein function.

During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of a target protein.

As a result, the target protein may change conformation, or the phosphorylated region can act as a novel binding site for other proteins.

These changes can modify the function of a protein,  completely activating or deactivating it.

The phosphate group can be removed by the action of protein phosphatases, enzymes that catalyze the dephosphorylation of proteins.

In this way, kinases and phosphatases can reversibly regulate the activity of certain proteins turning them on or off as and when required by the cell.