Post-Translational Modifications of Proteins

After their translation, many nascent proteins must be folded (this may require helper proteins called chaperonins) and further modified [local] to provide the final, functional form. Some of these modifications are the following

• Protein Targeting. Many proteins must be targeted within the cell (soluble compartment or membrane) or even targeted to the outside of the cell. The necessary information is usually built into the primary sequence of the protein, usually in the N-terminal sequence. Having arrived at its final location, this targeting sequence may be removed by proteolytic processing.
• Addition of bound cofactors or prosthetic groups
  • Many enzymes or proteins require a prosthetic group for activity. These cofactors must be added after translation. For example, the pyruvate dehydrogenase complex contains thiamine pyrophosphate and lipoic acid. Both of these cofactors must be added to the apoproteins in order to generate biochemical activity.

• Modification [local] of Amino Acid Residues. Here are examples:
  • Formation of disulfide linkages (2 -SH --> -S-S-). The oxidative crosslinking only occurs after the protein assumes a nearly correct tertiary structure.
  • Phosphorylation - Phosphorylation of hydrolylated (at Ser, Thr, and Tyr) residues and the imidazole of His are important in many cellular regulatory mechanisms related to energy metabolism and signal transduction.
  • Glycosylation [local] - Many extracellular proteins are glycosylated, often on amide nitrogen of Asp or hydroxyls of Thr or Ser residues.
  • Acetylation [local] - usually involves modification of N-terminal residues and impacts histone [local] binding to DNA
  • Carboxylation - Vitamin K is responsible for carboxylation of prothrombin, essential for blood clotting.
  • Adenylation. The addition of adenosine can control activities (e.g. glutamine synthetase [local]).
  • Hydroxylation - formation of hydroxyproline [local] in collagen.
  • Isoprenoid Addition [local] - Some proteins have prenyl lipid moieties attached.

• Proteolytic Processing. Some enzymes are produced as inactive precursors that are activated only after proteolytic cleavage of the precursor portion of the polypeptide chain. Two well-known examples are insulin [local] and the stomach digestive enzyme pepsin [local].

Protein lifetimes must also be regulated. This is an essential component of regulation. Some proteins are produced in response to some signal or nutrient and are not needed an hour later. Some enzymes are only needed at certain times in the cell cycle and would be disruptive at other times. Protein halflife in eukaryotic cells is correlated with the N-terminal amino acid. Some amino acids (e.g. Arg, Tyr, Ile, Leu, Lys, His, Phe, Trp, ) decrease the lifetime of the proteins and increase the turnover. Eukaryotic protein turnover also involves a protein called ubiquitin, which binds to proteins scheduled for turnover. These proteins are unfolded in an ATP-requiring process and degraded. The complex of ubiquitin plus protein is termed a proteosome [local].