Post-translational modification
In
Post-translational modifications can occur on the
Other forms of post-translational modification consist of cleaving
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
Post-translational modification of proteins can be experimentally detected by a variety of techniques, including
PTMs involving addition of functional groups
Addition by an enzyme in vivo
Hydrophobic groups for membrane localization
- myristate, a C14 saturated acid
- palmitate, a C16 saturated acid
- isoprenoid group (e.g. farnesol and geranylgeraniol)
- farnesylation
- geranylgeranylation
- glycosylphosphatidylinositol (GPI) anchorformation via an amide bond to C-terminal tail
Cofactors for enhanced enzymatic activity
- lipoate(C8) functional group
- flavin moiety (FMN or FAD) may be covalently attached
- 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 baseformation
Modifications of translation factors
- diphthamide formation (on a histidine found in eEF2)
- ethanolamine phosphoglycerol attachment (on glutamate found in eEF1α)[8]
- 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.[9] EFP is a homolog to eIF5A (eukaryotic) and aIF5A (archaeal) (see above).
Smaller chemical groups
- thioesters)
- deacetylation.
- formylation
- methyl, ethyl
- .
- amidation at C-terminus. Formed by oxidative dissociation of a C-terminal Gly residue.[11]
- amide bond formation
- amino acid addition
- tRNA-mediation addition
- polyglutamylation, covalent linkage of glutamic acid residues to the N-terminus of tubulin and some other proteins.[12] (See tubulin polyglutamylase)
- polyglycylation, covalent linkage of one to more than 40 glycine residues to the tubulin C-terminal tail
- amino acid addition
- butyrylation
- 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.
- O-GlcNAc, addition of N-acetylglucosamine to serine or threonine residues in a β-glycosidic linkage
- polysialylation, addition of NCAM
- malonylation
- 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
- phosphorylation, the addition of a phosphate group, usually to serine, threonine, and tyrosine (O-linked), or histidine (N-linked)
- (N-linked)
- uridylylation, the addition of an uridylyl-group (i.e. uridine monophosphate, UMP), usually to tyrosine
- propionylation
- pyroglutamateformation
- S-glutathionylation
- S-nitrosylation
- S-sulfenylation (aka S-sulphenylation), reversible covalent addition of one oxygen atom to the thiol group of a cysteine residue[14]
- S-sulfinylation, normally irreversible covalent addition of two oxygen atoms to the thiol group of a cysteine residue[14]
- 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[14]
- succinyl group to lysine
- sulfation, the addition of a sulfate group to a tyrosine.
Non-enzymatic modifications in vivo
Examples of non-enzymatic PTMs are glycation, glycoxidation, nitrosylation, oxidation, succination, and lipoxidation.[15]
- 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.[16]
- 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.[17]
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.[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 peptides
- covalentlinkage to the protein ubiquitin.
- SUMOylation, the covalent linkage to the SUMO protein (Small Ubiquitin-related MOdifier)[19]
- neddylation, the covalent linkage to the Nedd protein
- ISGylation, the covalent linkage to the ISG15 protein (Interferon-Stimulated Gene 15)[20]
- pupylation, the covalent linkage to the prokaryotic ubiquitin-like protein
Chemical modification of amino acids
- citrullination, or deimination, the conversion of arginine to citrulline[21]
- deamidation, the conversion of glutamine to glutamic acid or asparagine to aspartic acid
Structural changes
- disulfide bridges, the covalent linkage of two cysteineamino acids
- lysine-cysteine bridges, the covalent linkage of 1 lysine and 1 or 2 cystine residues via an oxygen atom (NOS and SONOS bridges)[23]
- proteolytic cleavage, cleavage of a protein at a peptide bond
- isoaspartate formation, via the cyclisation of asparagine or aspartic acid amino-acid residues
- racemization
- of serine by protein-serine epimerase
- of alanine in dermorphin, a frog opioid peptide
- of methionine in deltorphin, also a frog opioid peptide
- inteinsanalogous to mRNA processing
Statistics
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.
Databases and tools
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
- PhosphoSitePlus[27] – A database of comprehensive information and tools for the study of mammalian protein post-translational modification
- ProteomeScout[28] – A database of proteins and post-translational modifications experimentally
- Human Protein Reference Database[28] – A database for different modifications and understand different proteins, their class, and function/process related to disease causing proteins
- PROSITE[29] – A database of Consensus patterns for many types of PTM's including sites
- RESID[30] – A database consisting of a collection of annotations and structures for PTMs.
- iPTMnet [31]– A database that integrates PTM information from several knowledgbases and text mining results.
- dbPTM[26] – 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.
- The O-GlcNAc Database[33][34] - A curated database for protein O-GlcNAcylation and referencing more than 14 000 protein entries and 10 000 O-GlcNAc sites.
Tools
List of software for visualization of proteins and their PTMs
- PyMOL[35] – introduce a set of common PTM's into protein models
- AWESOME[36] – Interactive tool to see the role of single nucleotide polymorphisms to PTM's
- Chimera[37] – Interactive Database to visualize molecules
Case examples
This section needs additional citations for verification. (January 2016) |
- Cleavage and formation of disulfide bridges during the production of insulin
- PTM of RNA polymerase control by chromatin structure
- PTM of RNA polymerase II as regulation of transcription
- Cleavage of polypeptide chains as crucial for lectin specificity[38]
See also
References
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- ^ "The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity" PMID 33203089 PMC7696601
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- ^ "Proteome-Wide Post-Translational Modification Statistics". selene.princeton.edu. Archived from the original on 2012-08-30. Retrieved 2011-07-22.
- ^ PMID 16381945.
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- ^ "1tp8 - Proteopedia, life in 3D". www.proteopedia.org.
External links
(Wayback Machine copy)
- 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
(Wayback Machine copy)
- 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