When a protein is synthesized, the translational machinery, and for that matter, the genetic template, is limited to 20 natural amino acids. While these amino acids are able to cover a large spectrum of physical properties and chemical activities, some proteins require functional groups in addition to these. Many proteins, once synthesized, may undergo posttranslational modification. As one can deduce from the name, this term describes processes that occur after translation.

One basic form of posttranslational modification is proteolytic processing. A number of proteins are synthesize in an inactive form. They can then be actived by another protein, a protease, which cuts the inactive protein at specific sites. This liberates a smaller part of the protein which is now active. The inactive protein is called a proenzyme or zymogen. Insulin is a classic example of this type of modification.

Other modifications are the addition of new chemical groups to a protein:

  • N-glycosylation: Occurs in proteins with the internal sequence -Asn-Xaa-Ser/Thr where Xaa can be any amino acid. It entails the addition of complex sugars the the Asn sidechain. This normally occurs within the lumen of the Endoplasmic Reticulum (ER). Small peptides can also be glycosylated, suggesting that this process usually occurs before the protein folds. N-glycosylation can have roles in protein processing and recognition. Glycosylation can sometimes form a protective sugar coat around a protein that enters harsh environments. Many proteins in lysosomes such as LAMPs can withstand the acidic pH conditions used to digest protein waste. Many proteins are not active without glycosylation and some proteins wont even fold without the attached sugars.
  • disulfide formation: proteins are generated with free Cys residues, but during protein folding, pairs of cysteines can form disulfide bonds, providing covalent bridges that tie distant parts of a protein together. Some suggest that these interactions confer significant stability to a protein.
    		Cys - SH   HS - Cys       - two free cysteines
    					    S = sulfur
    		Cys-S-S-Cys		  - disulfide
  • prolyl-4-hydroxylation: In proteins with high incidence of proline such as collagen where sequence is (-Xaa-Yaa-Gly-)n, and X and Y are often proline, there is a high incidence of 4-hydroxylation at the Yaa proline. This reaction is usually catalyzed by an oxygen anion or iron anion. This modification is important in stabilizing the triple helix conformation that collagen adopts.
  • gamma-carboxylation: Occurs often at glutamine for proteins in the blood coagulation system and other proteins that have a high Ca++ affinity. This reaction requires Vitamin K as a cofactor.
  • cofactors: A number of proteins have chemical cofactors such as porphoryns, hemes, flavins, etc., that give the protein additional chemical functionality. These groups are often involved in electron transfer reactions.
There are far more posttranslational modifications than the ones listed here, and I will continue to add them as I find them.

Changes in the composition or structure of a protein often occur after translation. More often than not, these modifications are necessary for that protein to function properly. A lot of them are reversible.

Types of PTM

There are many types of post-translational modification. These are just a few of the common ones.


Enzyme catalyzed reactions are usually the source of modifications. Each amino acid in a protein has certain modifications that it is prone to. Only cysteine can form disulfide bridges. Not all modifications involve changes to the side chains of amino acids. Peptidases, enzymes that cut other proteins in half, attack at points with a specific amino acid sequence. Many modifications happen at the C or N terminus of a protein.


It is pretty easy to express any protein, but ensuring that it has the proper modifications can be extremely difficult. As stated before, most proteins will not do their job if they do not have the proper modifications. This is true of miraculin and conotoxins. Many modifications are used for both intracellular and intercellular signaling. Proteolytic cleavage performed by a signal peptidase is used to remove the signal peptide from a protein that will reside in the membrane or be secreted from the cell. Other modifications, like phosphorylation, are used to store energy. Conventional proteomics may not provide as much useful data as its advocates claim because modifications are not detected. Unwanted modifications may render a protein useless or cause it to malfunction.

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