4.11: Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases adds phosphate groups to a protein substrate. Kinases phosphorylate their targets by transferring the terminal phosphate group of ATP (or GTP) to its substrate. Protein kinases belong to an extensive family of enzymes that share a catalytic domain of 290 amino acids. Within a protein, phosphorylation can occur on several different amino acids. Based on their target substrates, protein kinases can be classified as histidine kinases, serine-threonine kinases, and tyrosine kinases.
Phosphatases reverse kinase activity by removing phosphate groups from their substrates through hydrolysis of phosphoric acid monoesters into a phosphate ion, leaving behind a free hydroxyl group. Protein phosphatases are structurally and functionally diverse and classified into four major groups depending on their catalytic mechanism, inhibitor sensitivity, and substrate preference. These categories include phosphoprotein phosphatases (PPP), phosphotyrosine phosphatases (PTP), Mg2+/Mn2+-dependent protein phosphatases (PPM), and aspartate-based protein phosphatases.
Activity and role of protein kinases and phosphatases
Protein kinases and phosphatases act as molecular switches. Some of these enzymes help maintain cellular homeostasis by sensing an optimum ATP:ADP ratio within cells. A reduced ATP:ADP reflects compromised energy status, triggering protein kinase activity. Protein kinases catalyze the phosphorylation of proteins, stimulating ATP-producing pathways. Conversely, protein phosphatases sense high ATP:ADP levels and catalyze the dephosphorylation of target proteins. Together these enzymes modulate critical pathways and processes in the cell, often in response to external stimuli.