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Post-translational modification

From Wikipedia, the free encyclopedia
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

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Addition by an enzyme in vivo

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Hydrophobic groups for membrane localization

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Cofactors for enhanced enzymatic activity

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Modifications of translation factors

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Smaller chemical groups

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Non-enzymatic modifications in vivo

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

Non-enzymatic additions in vitro

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  • 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

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Chemical modification of amino acids

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Structural changes

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Statistics

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Common PTMs by frequency

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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

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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

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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

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  • 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

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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

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See also

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References

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  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.
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  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.
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(Wayback Machine copy)

(Wayback Machine copy)