Post-translational modification

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Posttranslational modification
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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

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

lipidation, often targets a protein or part of a protein attached to the cell membrane
.

Other forms of post-translational modification consist of cleaving

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

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

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

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.

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
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
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
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

  • 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.
    Effect of PTMs on protein function and physiological processes.[32]
  • 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

See also

References

External links

(Wayback Machine copy)

(Wayback Machine copy)