Post-translational modification (PTM) refers to the covalent and generally enzymatic modification of proteins following protein biosynthesis. 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.
Post-translational modifications can occur on the amino acid side chains or at the protein's C- or N- termini. They can extend the chemical repertoire of the 20 standard amino acids by modifying an existing functional group or introducing a new one such as phosphate. Phosphorylation is a very common mechanism for regulating the activity of enzymes and is the most common post-translational modification. Many eukaryotic 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. 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. Specific amino acid modifications can be used as biomarkers indicating oxidative damage.
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 methylenes in side chains.:12–14
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 sections.
- 1 PTMs involving addition of functional groups
- 2 Other proteins or peptides
- 3 Chemical modification of amino acids
- 4 Structural changes
- 5 Statistics
- 6 Case examples
- 7 See also
- 8 References
- 9 External links
PTMs involving addition of functional groups
Addition by an enzyme in vivo
Hydrophobic groups for membrane localization
- myristoylation (a type of acylation), attachment of myristate, a C14 saturated acid
- palmitoylation (a type of acylation), attachment of palmitate, a C16 saturated acid
- isoprenylation or prenylation, the addition of an isoprenoid group (e.g. farnesol and geranylgeraniol)
- glypiation, glycosylphosphatidylinositol (GPI) anchor formation via an amide bond to C-terminal tail
Cofactors for enhanced enzymatic activity
- lipoylation (a type of acylation), attachment of a lipoate (C8) functional group
- flavin moiety (FMN or FAD) may be covalently attached
- heme C attachment via thioether bonds with cysteines
- phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety from coenzyme A, as in fatty acid, polyketide, non-ribosomal peptide and leucine biosynthesis
- retinylidene Schiff base formation
Modifications of translation factors
- diphthamide formation (on a histidine found in eEF2)
- ethanolamine phosphoglycerol attachment (on glutamate found in eEF1α)
- hypusine formation (on conserved lysine of eIF5A (eukaryotic) and aIF5A (archaeal))
- beta-Lysine addition on a conserved lysine of the elongation factor P (EFP) in most bacteria. EFP is an homolog to eIF5A (eukaryotic) and aIF5A (archaeal) (see above).
Smaller chemical groups
- acylation, e.g. O-acylation (esters), N-acylation (amides), S-acylation (thioesters)
- alkylation, the addition of an alkyl group, e.g. methyl, ethyl
- amidation at C-terminus. Formed by oxidative dissociation of a C-terminal Gly residue.
- amide bond formation
- amino acid addition
- gamma-carboxylation dependent on Vitamin K
- glycosylation, the addition of a glycosyl group to either arginine, asparagine, cysteine, hydroxylysine, serine, threonine, tyrosine, or tryptophan resulting in a glycoprotein. Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars.
- hydroxylation: addition of an oxygen atom to the side-chain of a Pro or Lys residue
- iodination: addition of an iodine atom to the aromatic ring of a tyrosine residue (e.g. in thyroglobulin)
- nucleotide addition such as ADP-ribosylation
- phosphate ester (O-linked) or phosphoramidate (N-linked) formation
- pyroglutamate formation
- S-sulfenylation (aka S-sulphenylation), reversible covalent addition of one oxygen atom to the thiol group of a cysteine residue
- S-sulfinylation, normally irreversible covalent addition of two oxygen atoms to the thiol group of a cysteine residue
- S-sulfonylation, normally irreversible covalent addition of three oxygen atoms to the thiol group of a cysteine residue, resulting in the formation of a cysteic acid residue
- succinylation addition of a succinyl group to lysine
- sulfation, the addition of a sulfate group to a tyrosine.
Non-enzymatic additions in vivo
- glycation, the addition of a sugar molecule to a protein without the controlling action of an enzyme.
- carbamylation the addition of Isocyanic acid to a protein's N-terminus or the side-chain of Lys.
- carbonylation the addition of carbon monoxide to other organic/inorganic compounds.
- spontaneous isopeptide bond formation, as found in many surface proteins of Gram-positive bacteria.
Non-enzymatic additions in vitro
- 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.
- 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.
Other proteins or peptides
- ISGylation, the covalent linkage to the ISG15 protein (Interferon-Stimulated Gene 15)
- SUMOylation, the covalent linkage to the SUMO protein (Small Ubiquitin-related MOdifier)
- ubiquitination, the covalent linkage to the protein ubiquitin.
- Neddylation, the covalent linkage to Nedd
- Pupylation, the covalent linkage to the Prokaryotic ubiquitin-like protein
Chemical modification of amino acids
- citrullination, or deimination, the conversion of arginine to citrulline 
- deamidation, the conversion of glutamine to glutamic acid or asparagine to aspartic acid
- eliminylation, the conversion to an alkene by beta-elimination of phosphothreonine and phosphoserine, or dehydration of threonine and serine 
- disulfide bridges, the covalent linkage of two cysteine amino acids
- proteolytic cleavage, cleavage of a protein at a peptide bond
- isoaspartate formation, via the cyclisation of asparagine or aspartic acid amino-acid residues
- protein splicing, self-catalytic removal of inteins analogous to mRNA processing
Common PTMs by frequency
In 2011, statistics of each post-translational modification experimentally and putatively detected have been compiled using proteome-wide information from the Swiss-Prot database. The 10 most common experimentally found modifications were as follows:
|826||Pyrrolidone Carboxylic Acid|
More details can be found at http://selene.princeton.edu/PTMCuration/.
Common PTMs by residue
Some common post-translational modifications to specific amino-acid residues are shown below. Modifications occur on the side-chain unless indicated otherwise.
This section does not cite any sources. (January 2016) (Learn how and when to remove this template message)
- Cleavage and formation of disulfide bridges during the production of insulin
- PTM of histones as regulation of transcription: RNA polymerase control by chromatin structure
- PTM of RNA polymerase II as regulation of transcription
- Cleavage of polypeptide chains as crucial for lectin specificity
- Pratt, Donald Voet; Judith G. Voet; Charlotte W. (2006). Fundamentals of biochemistry : life at the molecular level (2. ed.). Hoboken, NJ: Wiley. ISBN 0-471-21495-7.
- Khoury, GA; Baliban, RC; Floudas, CA (13 September 2011). "Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database". Scientific Reports. 1. doi:10.1038/srep00090. PMC . PMID 22034591.
- Lodish, H; Berk, A; Zipursky, SL; et al. (2000). "17.6, Post-Translational Modifications and Quality Control in the Rough ER". Molecular Cell Biology (4th ed.). New York: W. H. Freeman. ISBN 0-7167-3136-3.
- Dalle-Donne, Isabella; Aldini, Giancarlo; Carini, Marina; Colombo, Roberto; Rossi, Ranieri; Milzani, Aldo (2006). "Protein carbonylation, cellular dysfunction, and disease progression". Journal of Cellular and Molecular Medicine. 10 (2): 389–406. doi:10.1111/j.1582-4934.2006.tb00407.x. PMC . PMID 16796807.
- Grimsrud, P. A.; Xie, H.; Griffin, T. J.; Bernlohr, D. A. (2008). "Oxidative Stress and Covalent Modification of Protein with Bioactive Aldehydes". Journal of Biological Chemistry. 283 (32): 21837–41. doi:10.1074/jbc.R700019200. PMC . PMID 18445586.
- Gianazza, E; Crawford, J; Miller, I (July 2007). "Detecting oxidative post-translational modifications in proteins". Amino Acids. 33 (1): 51–6. doi:10.1007/s00726-006-0410-2. PMID 17021655.
- Walsh,, Christopher T. (2006). Posttranslational modification of proteins : expanding nature's inventory. Englewood: Roberts and Co. Publ. ISBN 9780974707730.
- Whiteheart SW, Shenbagamurthi P, Chen L, et al. (1989). "Murine elongation factor 1 alpha (EF-1 alpha) is posttranslationally modified by novel amide-linked ethanolamine-phosphoglycerol moieties. Addition of ethanolamine-phosphoglycerol to specific glutamic acid residues on EF-1 alpha". J. Biol. Chem. 264 (24): 14334–41. PMID 2569467.
- Roy, H; Zou, SB; Bullwinkle, TJ; Wolfe, BS; Gilreath, MS; Forsyth, CJ; Navarre, WW; Ibba, M. "The tRNA synthetase paralog PoxA modifies elongation factor-P with (R)-β-lysine". Nat Chem Biol. 7: 667–9. doi:10.1038/nchembio.632. PMC . PMID 21841797.
- Polevoda B, Sherman F; Sherman (2003). "N-terminal acetyltransferases and sequence requirements for N-terminal acetylation of eukaryotic proteins". J Mol Biol. 325 (4): 595–622. doi:10.1016/S0022-2836(02)01269-X. PMID 12507466.
- Yang XJ, Seto E; Seto (2008). "Lysine acetylation: codified crosstalk with other posttranslational modifications". Mol Cell. 31 (4): 449–61. doi:10.1016/j.molcel.2008.07.002. PMC . PMID 18722172.
- Bártová E, Krejcí J, Harnicarová A, Galiová G, Kozubek S; Krejcí; Harnicarová; Galiová; Kozubek (2008). "Histone modifications and nuclear architecture: a review". J Histochem Cytochem. 56 (8): 711–21. doi:10.1369/jhc.2008.951251. PMC . PMID 18474937.
- Glozak MA, Sengupta N, Zhang X, Seto E; Sengupta; Zhang; Seto (2005). "Acetylation and deacetylation of non-histone proteins". Gene. 363: 15–23. doi:10.1016/j.gene.2005.09.010. PMID 16289629.
- Bradbury AF, Smyth DG (1991). "Peptide amidation". Trends Biochem Sci. 16 (3): 112–5. doi:10.1016/0968-0004(91)90044-v. PMID 2057999.
- Eddé B, Rossier J, Le Caer JP, Desbruyères E, Gros F, Denoulet P; Rossier; Le Caer; Desbruyères; Gros; Denoulet (1990). "Posttranslational glutamylation of alpha-tubulin". Science. 247 (4938): 83–5. Bibcode:1990Sci...247...83E. doi:10.1126/science.1967194. PMID 1967194.
- Walker CS, Shetty RP, Clark K, et al. (2001). "On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems. Animals can experience subvaginal hemototitis as a result of this linkage. Evidence for a gamma-glutamyl carboxylase in Drosophila". J. Biol. Chem. 276 (11): 7769–74. doi:10.1074/jbc.M009576200. PMID 11110799.
- Chung HS; et al. (2013). "Cysteine Oxidative Posttranslational Modifications: Emerging Regulation in the Cardiovascular System". Circ. Res. 112: 382–392. doi:10.1161/CIRCRESAHA.112.268680.
- Jaisson S, Pietrement C, Gillery P (2011). "Carbamylation-Derived Products: Bioactive Compounds and Potential Biomarkers in Chronic Renal Failure and Atherosclerosis". Clin Chem. 57 (11): 1499–1505. doi:10.1373/clinchem.2011.163188. PMID 21768218.
- Kang HJ, Baker EN (2011). "Intramolecular isopeptide bonds: protein crosslinks built for stress?". Trends Biochem Sci. 36 (4): 229–237. doi:10.1016/j.tibs.2010.09.007. PMID 21055949.
- Stark GR, Stein WH, Moore X (1960). "Reactions of the Cyanate Present in Aqueous Urea with Amino Acids and Proteins". J Biol Chem. 235 (11): 3177–3181.
- Malakhova, Oxana A.; Yan, Ming; Malakhov, Michael P.; Yuan, Youzhong; Ritchie, Kenneth J.; Kim, Keun Il; Peterson, Luke F.; Shuai, Ke & Dong-Er Zhang (2003). "Protein ISGylation modulates the JAK-STAT signaling pathway". Genes & Development. 17 (4): 455–60. doi:10.1101/gad.1056303. PMC . PMID 12600939.
- Van G. Wilson (Ed.) (2004). Sumoylation: Molecular Biology and Biochemistry Archived 2005-02-09 at the Wayback Machine.. Horizon Bioscience. ISBN 0-9545232-8-8.
- Klareskog L; Rönnelid J; Lundberg K; Padyukov L; Alfredsson L (2008). "Immunity to citrullinated proteins in rheumatoid arthritis". Annu Rev Immunol. 26: 651–675. doi:10.1146/annurev.immunol.26.021607.090244. PMID 18173373.
- Brennan DF, Barford D; Barford (2009). "Eliminylation: a post-translational modification catalyzed by phosphothreonine lyases". Trends in Biochemical Sciences. 34 (3): 108–114. doi:10.1016/j.tibs.2008.11.005. PMID 19233656.
- Khoury, George A.; Baliban, Richard C. & Christodoulos A. Floudas (2011). "Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database". Scientific Reports. 1 (90): 90. Bibcode:2011NatSR...1E..90K. doi:10.1038/srep00090. PMC . PMID 22034591.
- dbPTM - database of protein post-translational modifications
- List of posttranslational modifications in ExPASy
- Browse SCOP domains by PTM — from the dcGO database
- Statistics of each post-translational modification from the Swiss-Prot database
- AutoMotif Server - A Computational Protocol for Identification of Post-Translational Modifications in Protein Sequences
- Functional analyses for site-specific phosphorylation of a target protein in cells
- Detection of Post-Translational Modifications after high-accuracy MSMS
- Overview and description of commonly used post-translational modification detection techniques