Post-translational modification ofinsulin. At the top, the ribosome translates a mRNA sequence into a protein, insulin, and passes the protein through theendoplasmic reticulum, where it is cut, folded, and held in shape by disulfide (-S-S-) bonds. Then the protein passes through thegolgi 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 (PTMs) are thecovalent processes of changingproteins following theirsynthesis, and release fromribosomes. PTMs are reversible editing events used and carried out in the overall process ofpost-translational regulation – thecontrol of the levels of active protein; an irreversible event isproteolysis (protein degradation). PTMs enable the protein's function to be diversified and extended beyond the dictates oftranscription.[1] As of 2023 there are more than 650 known types of PTM.[2] PTMs are alsoprokaryotic processes.[3]
PTMs may involveenzymes or occur spontaneously. Proteins are created by ribosomes, whichtranslatemRNA intopolypeptide chains, which may then change to form the mature protein product, which is then released from the ribosome. PTMs are important components incell signalling, as for example whenprohormones are converted tohormones.
Post-translational modifications can occur on theamino acidside chains or at the protein'sC- orN- termini.[4] They can expand the chemical set of the 22amino acids by changing an existingfunctional 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.[5] Manyeukaryotic andprokaryotic proteins also havecarbohydrate molecules attached to them in a process calledglycosylation, which can promoteprotein folding and improve stability as well as serving regulatory functions. Attachment oflipid molecules, known aslipidation, often targets a protein or part of a protein attached to thecell membrane.
Other forms of post-translational modification consist of cleavingpeptide bonds, as in processing apropeptide to a mature form or removing the initiatormethionine residue. The formation ofdisulfide bonds fromcysteine residues may also be referred to as a post-translational modification.[6] For instance, the peptidehormoneinsulin is cut twice after disulfide bonds are formed, and apropeptide 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 ofoxidative stress.Carbonylation is one example that targets the modified protein for degradation and can result in the formation of protein aggregates.[7][8] Specific amino acid modifications can be used asbiomarkers indicating oxidative damage.[9]PTMs and metal ions play a crucial and reciprocal role in regulating protein function, influencing cellular processes such as signal transduction and gene expression, with dysregulated interactions implicated in diseases like cancer and neurodegenerative disorders.[10]
phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety fromcoenzyme A, as in fatty acid, polyketide, non-ribosomal peptide and leucine biosynthesis
S-sulfenylation (akaS-sulphenylation), reversible covalent addition of one oxygen atom to thethiol group of acysteine residue[18]
S-sulfinylation, normally irreversible covalent addition of two oxygen atoms to thethiol group of acysteine residue[18]
S-sulfonylation, normally irreversible covalent addition of three oxygen atoms to thethiol group of acysteine residue, resulting in the formation of acysteic acid residue[18]
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.[26]
oxidation: addition of one or more oxygen atoms to a susceptible side-chain, principally of Met, Trp, His or Cys residues. Formation ofdisulfide bonds between Cys residues.
pegylation: covalent attachment ofpolyethylene 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.[32] The 10 most common experimentally found modifications were as follows:[33]
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.[34]
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.
PhosphoSitePlus[35] – A database of comprehensive information and tools for the study of mammalian protein post-translational modification
ProteomeScout[36] – A database of proteins and post-translational modifications experimentally
Human Protein Reference Database[36] – A database for different modifications and understand different proteins, their class, and function/process related to disease causing proteins
PROSITE[37] – A database of Consensus patterns for many types of PTM's including sites
RESID[38] – A database consisting of a collection of annotations and structures for PTMs.
iPTMnet[39]– A database that integrates PTM information from several knowledgbases and text mining results.
dbPTM[34] – 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.[40]
TheO-GlcNAc Database[41][42] - A curated database for protein O-GlcNAcylation and referencing more than 14 000 protein entries and 10 000O-GlcNAc sites.
^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.
^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.PMID19233656.
