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.

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

Post-translational modifications can occur on the amino acid side chains or at the protein's C- or N- termini.[1] They can expand the chemical set of the 22 amino acids by changing an existing functional group or adding a new one such as phosphate. Phosphorylation is highly effective for controlling the enzyme activity and is the most common change after translation. [2] 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.[3] 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.[4][5] Specific amino acid modifications can be used as biomarkers indicating oxidative damage.[6]

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.[7]

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 groups

Addition by an enzyme in vivo

Hydrophobic groups for membrane localization

Cofactors for enhanced enzymatic activity

Modifications of translation factors

Smaller chemical groups

Non-enzymatic modifications in vivo

Examples of non-enzymatic PTMs are glycation, glycoxidation, nitrosylation, oxidation, succination, and lipoxidation.[15]

Non-enzymatic additions in vitro

Conjugation with other proteins or peptides

Chemical modification of amino acids

Structural changes


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.[24] The 10 most common experimentally found modifications were as follows:[25]

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 residue

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 or A N-acetylation (N-terminus)
Arginine Arg or R deimination to citrulline, methylation
Asparagine Asn or N deamidation to Asp or iso(Asp), N-linked glycosylation, spontaneous isopeptide bond formation
Aspartic acid Asp or D isomerization to isoaspartic acid, spontaneous isopeptide bond formation
Cysteine Cys or C disulfide-bond formation, oxidation to sulfenic, sulfinic or sulfonic acid, palmitoylation, N-acetylation (N-terminus), S-nitrosylation
Glutamine Gln or Q cyclization to pyroglutamic acid (N-terminus), deamidation to Glutamic acid or isopeptide bond formation to a lysine by a transglutaminase
Glutamic acid Glu or E cyclization to Pyroglutamic acid (N-terminus), gamma-carboxylation
Glycine Gly or G N-Myristoylation (N-terminus), N-acetylation (N-terminus)
Histidine His or H Phosphorylation
Isoleucine Ile or I
Leucine Leu or L
Lysine Lys or K acetylation, ubiquitylation, SUMOylation, methylation, hydroxylation leading to allysine, spontaneous isopeptide bond formation
Methionine Met or M N-acetylation (N-terminus), N-linked Ubiquitination, oxidation to sulfoxide or sulfone
Phenylalanine Phe or F
Proline Pro or P hydroxylation
Serine Ser or S Phosphorylation, O-linked glycosylation, N-acetylation (N-terminus)
Threonine Thr or T Phosphorylation, O-linked glycosylation, N-acetylation (N-terminus)
Tryptophan Trp or W mono- or di-oxidation, formation of kynurenine, tryptophan tryptophylquinone
Tyrosine Tyr or Y sulfation, phosphorylation
Valine Val or V N-acetylation (N-terminus)

Databases and tools

Flowchart of the process and the data sources to predict PTMs.[26]

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 resources


List of software for visualization of proteins and their PTMs

Case examples

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources in this section. Unsourced material may be challenged and removed. (January 2016) (Learn how and when to remove this message)

See also


  1. ^ Pratt, Charlotte W.; Voet, Judith G.; Voet, Donald (2006). Fundamentals of Biochemistry: Life at the Molecular Level (2nd ed.). Hoboken, NJ: Wiley. ISBN 9780471214953. OCLC 1280801548. Archived from the original on 13 July 2012.
  2. ^ Khoury GA, Baliban RC, Floudas CA (September 2011). "Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database". Scientific Reports. 1: 90. Bibcode:2011NatSR...1E..90K. doi:10.1038/srep00090. PMC 3201773. PMID 22034591.
  3. ^ 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 978-0-7167-3136-8.
  4. ^ Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (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 3933129. PMID 16796807.
  5. ^ Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA (August 2008). "Oxidative stress and covalent modification of protein with bioactive aldehydes". The Journal of Biological Chemistry. 283 (32): 21837–41. doi:10.1074/jbc.R700019200. PMC 2494933. PMID 18445586.
  6. ^ 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. S2CID 23819101.
  7. ^ Walsh, Christopher T. (2006). Posttranslational modification of proteins : expanding nature's inventory. Englewood: Roberts and Co. Publ. ISBN 9780974707730. : 12–14 
  8. ^ Whiteheart SW, Shenbagamurthi P, Chen L, Cotter RJ, Hart GW, et al. (August 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". The Journal of Biological Chemistry. 264 (24): 14334–41. doi:10.1016/S0021-9258(18)71682-7. PMID 2569467.
  9. ^ Roy H, Zou SB, Bullwinkle TJ, Wolfe BS, Gilreath MS, Forsyth CJ, Navarre WW, Ibba M (August 2011). "The tRNA synthetase paralog PoxA modifies elongation factor-P with (R)-β-lysine". Nature Chemical Biology. 7 (10): 667–9. doi:10.1038/nchembio.632. PMC 3177975. PMID 21841797.
  10. ^ Ali I, Conrad RJ, Verdin E, Ott M (February 2018). "Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics". Chem Rev. 118 (3): 1216–1252. doi:10.1021/acs.chemrev.7b00181. PMC 6609103. PMID 29405707.
  11. ^ Bradbury AF, Smyth DG (March 1991). "Peptide amidation". Trends in Biochemical Sciences. 16 (3): 112–5. doi:10.1016/0968-0004(91)90044-v. PMID 2057999.
  12. ^ Eddé B, Rossier J, Le Caer JP, Desbruyères E, Gros F, Denoulet P (January 1990). "Posttranslational glutamylation of alpha-tubulin". Science. 247 (4938): 83–5. Bibcode:1990Sci...247...83E. doi:10.1126/science.1967194. PMID 1967194.
  13. ^ Walker CS, Shetty RP, Clark K, Kazuko SG, Letsou A, Olivera BM, Bandyopadhyay PK, et al. (March 2001). "On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems. Evidence for a gamma-glutamyl carboxylase in Drosophila". The Journal of Biological Chemistry. 276 (11): 7769–74. doi:10.1074/jbc.M009576200. PMID 11110799.
  14. ^ a b c Chung HS, et al. (January 2013). "Cysteine oxidative posttranslational modifications: emerging regulation in the cardiovascular system". Circulation Research. 112 (2): 382–92. doi:10.1161/CIRCRESAHA.112.268680. PMC 4340704. PMID 23329793.
  15. ^ "The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity" PMID 33203089 PMC7696601
  16. ^ Jaisson S, Pietrement C, Gillery P (November 2011). "Carbamylation-derived products: bioactive compounds and potential biomarkers in chronic renal failure and atherosclerosis". Clinical Chemistry. 57 (11): 1499–505. doi:10.1373/clinchem.2011.163188. PMID 21768218.
  17. ^ Kang HJ, Baker EN (April 2011). "Intramolecular isopeptide bonds: protein crosslinks built for stress?". Trends in Biochemical Sciences. 36 (4): 229–37. doi:10.1016/j.tibs.2010.09.007. PMID 21055949.
  18. ^ 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. doi:10.1016/S0021-9258(20)81332-5.
  19. ^ 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.
  20. ^ Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, Peterson LF, Shuai K, Zhang DE (February 2003). "Protein ISGylation modulates the JAK-STAT signaling pathway". Genes & Development. 17 (4): 455–60. doi:10.1101/gad.1056303. PMC 195994. PMID 12600939.
  21. ^ Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L (2008). "Immunity to citrullinated proteins in rheumatoid arthritis". Annual Review of Immunology. 26: 651–75. doi:10.1146/annurev.immunol.26.021607.090244. PMID 18173373.
  22. ^ Brennan DF, Barford D (March 2009). "Eliminylation: a post-translational modification catalyzed by phosphothreonine lyases". Trends in Biochemical Sciences. 34 (3): 108–14. doi:10.1016/j.tibs.2008.11.005. PMID 19233656.
  23. ^ Rabe von Pappenheim, Fabian; Wensien, Marie; Ye, Jin; Uranga, Jon; Irisarri, Iker; de Vries, Jan; Funk, Lisa-Marie; Mata, Ricardo A.; Tittmann, Kai (April 2022). "Widespread occurrence of covalent lysine–cysteine redox switches in proteins". Nature Chemical Biology. 18 (4): 368–375. doi:10.1038/s41589-021-00966-5. PMC 8964421.
  24. ^ Khoury GA, Baliban RC, Floudas CA (September 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 3201773. PMID 22034591.
  25. ^ "Proteome-Wide Post-Translational Modification Statistics". Archived from the original on 2012-08-30. Retrieved 2011-07-22.
  26. ^ a b Lee TY, Huang HD, Hung JH, Huang HY, Yang YS, Wang TH (January 2006). "dbPTM: an information repository of protein post-translational modification". Nucleic Acids Research. 34 (Database issue): D622-7. doi:10.1093/nar/gkj083. PMC 1347446. PMID 16381945.
  27. ^ Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E (January 2015). "PhosphoSitePlus, 2014: mutations, PTMs and recalibrations". Nucleic Acids Research. 43 (Database issue): D512-20. doi:10.1093/nar/gku1267. PMC 4383998. PMID 25514926.
  28. ^ a b Goel R, Harsha HC, Pandey A, Prasad TS (February 2012). "Human Protein Reference Database and Human Proteinpedia as resources for phosphoproteome analysis". Molecular BioSystems. 8 (2): 453–63. doi:10.1039/c1mb05340j. PMC 3804167. PMID 22159132.
  29. ^ Sigrist CJ, Cerutti L, de Castro E, Langendijk-Genevaux PS, Bulliard V, Bairoch A, Hulo N (January 2010). "PROSITE, a protein domain database for functional characterization and annotation". Nucleic Acids Research. 38 (Database issue): D161-6. doi:10.1093/nar/gkp885. PMC 2808866. PMID 19858104.
  30. ^ Garavelli JS (January 2003). "The RESID Database of Protein Modifications: 2003 developments". Nucleic Acids Research. 31 (1): 499–501. doi:10.1093/nar/gkg038. PMC 165485. PMID 12520062.
  31. ^ Huang H, Arighi CN, Ross KE, Ren J, Li G, Chen SC, Wang Q, Cowart J, Vijay-Shanker K, Wu CH (January 2018). "iPTMnet: an integrated resource for protein post-translational modification network discovery". Nucleic Acids Research. 46 (1): D542–D550. doi:10.1093/nar/gkx1104. PMC 5753337. PMID 2914561.
  32. ^ Audagnotto M, Dal Peraro M (2017-03-31). "In silico prediction tools and molecular modeling". Computational and Structural Biotechnology Journal. 15: 307–319. doi:10.1016/j.csbj.2017.03.004. PMC 5397102. PMID 28458782.
  33. ^ Wulff-Fuentes E, Berendt RR, Massman L, Danner L, Malard F, Vora J, Kahsay R, Olivier-Van Stichelen S (January 2021). "The human O-GlcNAcome database and meta-analysis". Scientific Data. 8 (1): 25. Bibcode:2021NatSD...8...25W. doi:10.1038/s41597-021-00810-4. PMC 7820439. PMID 33479245.
  34. ^ Malard F, Wulff-Fuentes E, Berendt RR, Didier G, Olivier-Van Stichelen S (July 2021). "Automatization and self-maintenance of the O-GlcNAcome catalog: a smart scientific database". Database (Oxford). 2021: 1. doi:10.1093/database/baab039. PMC 8288053. PMID 34279596.
  35. ^ Warnecke A, Sandalova T, Achour A, Harris RA (November 2014). "PyTMs: a useful PyMOL plugin for modeling common post-translational modifications". BMC Bioinformatics. 15 (1): 370. doi:10.1186/s12859-014-0370-6. PMC 4256751. PMID 25431162.
  36. ^ Yang Y, Peng X, Ying P, Tian J, Li J, Ke J, Zhu Y, Gong Y, Zou D, Yang N, Wang X, Mei S, Zhong R, Gong J, Chang J, Miao X (January 2019). "AWESOME: a database of SNPs that affect protein post-translational modifications". Nucleic Acids Research. 47 (D1): D874–D880. doi:10.1093/nar/gky821. PMC 6324025. PMID 30215764.
  37. ^ Morris JH, Huang CC, Babbitt PC, Ferrin TE (September 2007). "structureViz: linking Cytoscape and UCSF Chimera". Bioinformatics. 23 (17): 2345–7. doi:10.1093/bioinformatics/btm329. PMID 17623706.
  38. ^ "1tp8 - Proteopedia, life in 3D".

(Wayback Machine copy)

(Wayback Machine copy)