Covalently Linked Protein Regulators

Many proteins are regulated by covalently linked molecules, including functional groups, such as methyl or acetyl moieties, and small proteins, such as ubiquitin.

Covalent linkages occur on specific amino acids in the polypeptide chain. For example, phosphate groups are covalently linked to serine, threonine, or tyrosine; methyl and acetyl groups are linked to lysine; and ubiquitin is linked to lysine, cysteine, serine, or threonine residues.

An enzyme or pair of enzymes reversibly catalyzes these post-translational modifications.  An acetyltransferase can acetylate a protein, while a deacetylase can later remove the group.

These modifications can alter a protein’s function or localization in a cell.

For example, acetylation of histone proteins regulates gene expression by opening up the DNA structure to activate gene transcription. Methylation of histone proteins, on the other hand, is known to repress transcription by tightening the structure. 

Another example is p53, a multidomain tumor suppressor protein that undergoes several covalent modifications in response to stress. Exposure to DNA damaging agents, such as UV and gamma radiation, can result in phosphorylation of the protein. 

Phosphorylation improves stability and activates p53, causing it to bind to DNA damaged by the radiation and prevents cells with mutated DNA from dividing uncontrollably.

In addition to phosphorylation, different types of modifications occurring on a single protein molecule, such as p53, allow it to precisely control its functions such as cell cycle arrest, DNA repair, and apoptosis of a cell.