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.
Post-translational modifications can occur on the amino acidside 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 hormoneinsulin 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]
phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety from coenzyme A, as in fatty acid, polyketide, non-ribosomal peptide and leucine biosynthesis
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).
S-sulfenylation (akaS-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]
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.
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]
Some common post-translational modifications to specific amino-acid residues are shown below. Modifications occur on the side-chain unless indicated otherwise.
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
This section needs additional citations for verification. (January 2016)
Walsh, Christopher T. (2006). Posttranslational modification of proteins: expanding nature's inventory. Englewood: Roberts and Co. Publ. ISBN9780974707730. :12–14
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. PMID21055949.
