Post-translational modification

Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process often occurs in the endoplasmic reticulum and the golgi apparatus.[1] Proteins are synthesized by ribosomes translating mRNA into polypeptide chains, which may then undergo PTM to form the mature protein product. PTMs are important components in cell signaling, as for example when prohormones are converted to hormones.

Post-translational modification of insulin. At the top, the ribosome translates a mRNA sequence into a protein, insulin, and passes the protein through the endoplasmic reticulum, where it is cut, folded, and held in shape by disulfide (-S-S-) bonds. Then the protein passes through the golgi apparatus, where it is packaged into a vesicle. In the vesicle, more parts are cut off, and it turns into mature insulin.

Post-translational modifications can occur on the amino acid side chains or at the protein's C- or N- termini.[2] They can extend the chemical repertoire of the 22 proteinogenic amino acids by modifying an existing functional group or introducing a new one such as phosphate. Phosphorylation is a highly effective mechanism for regulating the activity of enzymes and is the most common post-translational modification.[3] Many eukaryotic and prokaryotic proteins also have carbohydrate molecules attached to them in a process called glycosylation, which can promote protein folding and improve stability as well as serving regulatory functions. Attachment of lipid molecules, known as lipidation, often targets a protein or part of a protein attached to the cell membrane.

Other forms of post-translational modification consist of cleaving peptide bonds, as in processing a propeptide to a mature form or removing the initiator methionine residue. The formation of disulfide bonds from cysteine residues may also be referred to as a post-translational modification.[4] For instance, the peptide hormone insulin is cut twice after disulfide bonds are formed, and a propeptide is removed from the middle of the chain; the resulting protein consists of two polypeptide chains connected by disulfide bonds.

Some types of post-translational modification are consequences of oxidative stress. Carbonylation is one example that targets the modified protein for degradation and can result in the formation of protein aggregates.[5][6] Specific amino acid modifications can be used as biomarkers indicating oxidative damage.[7]

Sites that often undergo post-translational modification are those that have a functional group that can serve as a nucleophile in the reaction: the hydroxyl groups of serine, threonine, and tyrosine; the amine forms of lysine, arginine, and histidine; the thiolate anion of cysteine; the carboxylates of aspartate and glutamate; and the N- and C-termini. In addition, although the amide of asparagine is a weak nucleophile, it can serve as an attachment point for glycans. Rarer modifications can occur at oxidized methionines and at some methylene groups in side chains.[8]

Post-translational modification of proteins can be experimentally detected by a variety of techniques, including mass spectrometry, Eastern blotting, and Western blotting. Additional methods are provided in the #External links section.

PTMs involving addition of functional groupsEdit

Addition by an enzyme in vivoEdit

Hydrophobic groups for membrane localizationEdit

Cofactors for enhanced enzymatic activityEdit

Modifications of translation factorsEdit

Smaller chemical groupsEdit

Non-enzymatic additions in vivoEdit

Non-enzymatic additions in vitroEdit

  • biotinylation: covalent attachment of a biotin moiety using a biotinylation reagent, typically for the purpose of labeling a protein.
  • carbamylation: the addition of Isocyanic acid to a protein's N-terminus or the side-chain of Lys or Cys residues, typically resulting from exposure to urea solutions.[18]
  • oxidation: addition of one or more Oxygen atoms to a susceptible side-chain, principally of Met, Trp, His or Cys residues. Formation of disulfide bonds between Cys residues.
  • pegylation: covalent attachment of polyethylene glycol (PEG) using a pegylation reagent, typically to the N-terminus or the side-chains of Lys residues. Pegylation is used to improve the efficacy of protein pharmaceuticals.

Conjugation with other proteins or peptidesEdit

Chemical modification of amino acidsEdit

Structural changesEdit


Common PTMs by frequencyEdit

In 2011, statistics of each post-translational modification experimentally and putatively detected have been compiled using proteome-wide information from the Swiss-Prot database.[23] The 10 most common experimentally found modifications were as follows:[24]

Frequency Modification
58383 Phosphorylation
6751 Acetylation
5526 N-linked glycosylation
2844 Amidation
1619 Hydroxylation
1523 Methylation
1133 O-linked glycosylation
878 Ubiquitylation
826 Pyrrolidone carboxylic acid
504 Sulfation

Common PTMs by residueEdit

Some common post-translational modifications to specific amino-acid residues are shown below. Modifications occur on the side-chain unless indicated otherwise.

Amino Acid Abbrev. Modification
Alanine Ala N-acetylation (N-terminus)
Arginine Arg deimination to citrulline, methylation
Asparagine Asn deamidation to Asp or iso(Asp), N-linked glycosylation
Aspartic acid Asp isomerization to isoaspartic acid
Cysteine Cys disulfide-bond formation, oxidation to sulfenic, sulfinic or sulfonic acid, palmitoylation, N-acetylation (N-terminus), S-nitrosylation
Glutamine Gln cyclization to pyroglutamic acid (N-terminus), deamidation to Glutamic acid or isopeptide bond formation to a lysine by a transglutaminase
Glutamic acid Glu cyclization to Pyroglutamic acid (N-terminus), gamma-carboxylation
Glycine Gly N-Myristoylation (N-terminus), N-acetylation (N-terminus)
Histidine His Phosphorylation
Isoleucine Ile
Leucine Leu
Lysine Lys acetylation, ubiquitylation, SUMOylation, methylation, hydroxylation leading to allysine
Methionine Met N-acetylation (N-terminus), N-linked Ubiquitination, oxidation to sulfoxide or sulfone
Phenylalanine Phe
Proline Pro hydroxylation
Serine Ser Phosphorylation, O-linked glycosylation, N-acetylation (N-terminus)
Threonine Thr Phosphorylation, O-linked glycosylation, N-acetylation (N-terminus)
Tryptophan Trp mono- or di-oxidation, formation of kynurenine, tryptophan tryptophylquinone
Tyrosine Tyr sulfation, phosphorylation
Valine Val N-acetylation (N-terminus)

Databases and toolsEdit

Flowchart of the process and the data sources to predict PTMs.[25]

Protein sequences contain sequence motifs that are recognized by modifying enzymes, and which can be documented or predicted in PTM databases. With the large number of different modifications being discovered, there is a need to document this sort of information in databases. PTM information can be collected through experimental means or predicted from high-quality, manually curated data. Numerous databases have been created, often with a focus on certain taxonomic groups (e.g. human proteins) or other features.

List of resourcesEdit

  • PhosphoSitePlus[26] – A database of comprehensive information and tools for the study of mammalian protein post-translational modification
  • ProteomeScout[27] – A database of proteins and post-translational modifications experimentally
  • Human Protein Reference Database[27] – A database for different modifications and understand different proteins, their class, and function/process related to disease causing proteins
  • PROSITE[28] – A database of Consensus patterns for many types of PTM's including sites
  • RESID[29] – A database consisting of a collection of annotations and structures for PTMs.
  • iPTMnet [30]– A database that integrates PTM information from several knowledgbases and text mining results.
  • dbPTM[25] – A database that shows different PTM's and information regarding their chemical components/structures and a frequency for amino acid modified site
  • Uniprot has PTM information although that may be less comprehensive than in more specialized databases.
    Effect of PTMs on protein function and physiological processes.[31]
  • The O-GlcNAc Database[32][33] - A curated database for protein O-GlcNAcylation and referencing more than 14 000 protein entries and 10 000 O-GlcNAc sites.


List of software for visualization of proteins and their PTMs

  • PyMOL[34] – introduce a set of common PTM's into protein models
  • AWESOME[35] – Interactive tool to see the role of single nucleotide polymorphisms to PTM's
  • Chimera[36] – Interactive Database to visualize molecules

Case examplesEdit

See alsoEdit


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External linksEdit

(Wayback Machine copy)

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