Posttranslational Modification
   HOME

TheInfoList



OR:

In
molecular biology Molecular biology is a branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, biomolecular synthesis, modification, mechanisms, and interactio ...
, post-translational modification (PTM) is the covalent process of changing
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s following protein biosynthesis. PTMs may involve
enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
or occur spontaneously. Proteins are created by ribosomes, which translate
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
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
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s. Post-translational modifications can occur on the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
s or at the protein's C- or N- termini. They can expand the chemical set of the 22
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
by changing an existing
functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
or adding a new one such as phosphate.
Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
is highly effective for controlling the enzyme activity and is the most common change after translation. Many
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
and prokaryotic proteins also have
carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...
molecules attached to them in a process called
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
, which can promote
protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...
and improve stability as well as serving regulatory functions. Attachment of
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
molecules, known as lipidation, often targets a protein or part of a protein attached to the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. 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. For instance, the peptide
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
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. Specific amino acid modifications can be used as biomarkers indicating oxidative damage. 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. 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 Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
, and
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
; the thiolate anion of cysteine; the carboxylates of aspartate and
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
; 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
glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...
s. Rarer modifications can occur at oxidized methionines and at some methylene groups in side chains. Post-translational modification of proteins can be experimentally detected by a variety of techniques, including mass spectrometry, Eastern blotting, and Western blotting.


PTMs involving addition of functional groups


Addition by an enzyme ''in vivo''


Hydrophobic groups for membrane localization

* myristoylation (a type of acylation), attachment of myristate, a C14 saturated acid * palmitoylation (a type of acylation), attachment of palmitate, a C16 saturated acid * isoprenylation or prenylation, the addition of an isoprenoid group (e.g. farnesol and geranylgeraniol) ** farnesylation ** geranylgeranylation * glypiation, glycosylphosphatidylinositol (GPI) anchor formation via an amide bond to C-terminal tail


Cofactors for enhanced enzymatic activity

* lipoylation (a type of acylation), attachment of a lipoate (C8) functional group * flavin moiety ( flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD)) may be covalently attached * heme C attachment via thioether bonds with cysteines * phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety from
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...
, as in fatty acid, polyketide, non-ribosomal peptide and leucine biosynthesis * retinylidene Schiff base formation


Modifications of translation factors

* diphthamide formation (on a histidine found in eEF2) * ethanolamine phosphoglycerol attachment (on glutamate found in eEF1α) * 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. EFP is a homolog to eIF5A (eukaryotic) and aIF5A (archaeal) (see above).


Smaller chemical groups

* acylation, e.g. ''O''-acylation (
esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...
), ''N''-acylation ( amides), ''S''-acylation ( thioesters) ** acetylation, the addition of an acetyl group, either at the N-terminus of the protein or at lysine residues. The reverse is called deacetylation. ** formylation *
alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...
, the addition of an
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...
group, e.g. methyl, ethyl ** methylation the addition of a methyl group, usually at lysine or
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
residues. The reverse is called
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
. * amidation at C-terminus. Formed by oxidative dissociation of a C-terminal Gly residue. * amide bond formation **
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
addition *** arginylation, a tRNA-mediation addition *** polyglutamylation, covalent linkage of glutamic acid residues to the N-terminus of tubulin and some other proteins. (See tubulin polyglutamylase) *** polyglycylation, covalent linkage of one to more than 40
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
residues to the tubulin C-terminal tail * butyrylation * gamma-carboxylation dependent on
Vitamin K Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-translational modification, post-synthesis modification of certain proteins ...
*
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
, the addition of a glycosyl group to either
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
, asparagine, cysteine, hydroxylysine, serine, threonine, tyrosine, or tryptophan resulting in a glycoprotein. Distinct from
glycation Glycation (non-enzymatic glycosylation) is the covalent bond, covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is th ...
, 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 polysialic acid (PSA) to neural cell adhesion molecule (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 In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
, the addition of a
phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
group, usually to serine, threonine, and tyrosine (''O''-linked), or
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
(''N''-linked) ** adenylylation, the addition of an adenylyl moiety, usually to tyrosine (''O''-linked), or
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
and lysine (''N''-linked) ** uridylylation, the addition of an uridylyl-group (i.e. uridine monophosphate (UMP)), usually to tyrosine * propionylation * pyroglutamate formation * ''S''-glutathionylation * ''S''-nitrosylation * ''S''-sulfenylation (''aka'' ''S''-sulphenylation), reversible covalent addition of one oxygen atom to the thiol group of a cysteine residue * ''S''-sulfinylation, normally irreversible covalent addition of two oxygen atoms to the thiol group of a cysteine residue * ''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 * succinylation addition of a 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. *
glycation Glycation (non-enzymatic glycosylation) is the covalent bond, covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is th ...
, 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. * 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 In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain ...
.


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. * 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 Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular wei ...
(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

* ubiquitination, the covalent linkage to the protein ubiquitin. * SUMOylation, the covalent linkage to the SUMO protein (small ubiquitin-related modifier) * neddylation, the covalent linkage to the Nedd protein * ISGylation, the covalent linkage to the ISG15 protein (interferon-stimulated gene 15) * pupylation, the covalent linkage to the prokaryotic ubiquitin-like protein


Chemical modification of amino acids

* citrullination, or deimination, the conversion of
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
to citrulline * deamidation, the conversion of glutamine to glutamic acid or asparagine to aspartic acid * eliminylation, the conversion to an alkene by beta-elimination of phosphothreonine and phosphoserine, or dehydration of threonine and serine


Structural changes

* disulfide bridges, the covalent linkage of two cysteine amino acids * lysine-cysteine bridges, the covalent linkage of 1 lysine and 1 or 2 cystine residues via an oxygen atom (NOS and SONOS bridges) * 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 * protein splicing, self-catalytic removal of inteins analogous 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. The 10 most common experimentally found modifications were as follows:


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
– A database of comprehensive information and tools for the study of mammalian protein post-translational modification * ProteomeScout – A database of proteins and post-translational modifications experimentally * Human Protein Reference Database – A database for different modifications and understand different proteins, their class, and function/process related to disease causing proteins * PROSITE – A database of Consensus patterns for many types of PTM's including sites * RESID – A database consisting of a collection of annotations and structures for PTMs.
iPTMnet
– A database that integrates PTM information from several knowledgbases and text mining results. * dbPTM – 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
- 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 – introduce a set of common PTM's into protein models * AWESOME – Interactive tool to see the role of single nucleotide polymorphisms to PTM's * Chimera – Interactive Database to visualize molecules


Case examples

* Cleavage and formation of disulfide bridges during the production of
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
* PTM of histones as regulation of transcription: RNA polymerase control by chromatin structure * PTM of
RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...
as regulation of transcription * Cleavage of polypeptide chains as crucial for lectin specificity * Influence of Ni(II) in the Acetylation of Histones H4 Protein


See also

* Protein targeting *
Post-translational regulation Post-translational regulation refers to the control of the levels of active protein. There are several forms. It is performed either by means of reversible events ( posttranslational modifications, such as phosphorylation In biochemistry, p ...


References


External links


Controlled vocabulary of post-translational modifications
in Uniprot
List of posttranslational modifications in ExPASy

Browse SCOP domains by PTM
— from the dcGO database
Overview and description of commonly used post-translational modification detection techniques
{{DEFAULTSORT:Posttranslational Modification Gene expression Protein structure Protein biosynthesis Cell biology