Post-translational modification

Post-translational modification (PTM) refers to the covalent and generally enzymatic modification of proteins following protein biosynthesis. Proteins are synthesized by ribosomes translating mRNA into polypeptide chains, which may then undergo PTM to form the mature protein product. PTMs are important components in cell signaling, 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. They can extend the chemical repertoire of the 20 standard amino acids by modifying an existing functional group or introducing a new one such as phosphate. Phosphorylation is a very common mechanism for regulating the activity of enzymes and is the most common post-translational modification. 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. 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. Specific amino acid modifications can be used as biomarkers indicating oxidative damage.
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 methylenes 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. Additional methods are provided in the external links sections.
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.
Tools.
List of software for visualization of proteins and their PTMs
Addiction.
A major feature of addiction is its persistence. The addictive phenotype can be lifelong, with drug craving and relapse occurring even after decades of abstinence. Post-translational modifications consisting of epigenetic alterations of histone protein tails in specific regions of the brain appear to be crucial to the molecular basis of addictions. Once particular post-translational epigenetic modifications occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.
Cigarette smokers (about 21% of the US population in 2013)) are usually addicted to nicotine. After 7 days of nicotine treatment of mice, the post-translational modifications consisting of acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing a 61% increase in FosB expression. This also increases expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction. Similarly, after 15 days of nicotine treatment of rats, the post-translational modification consisting of 3-fold increased acetylation of histone H4 occurs at the promoter of the dopamine D1 receptor (DRD1) gene in the prefrontal cortex (PFC) of the rats. This caused increased dopamine release in the PFC reward-related brain region, and such increased dopamine release is recognized as an important factor for addiction.
About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in the post-translational modification of histone 3 lysine 9 acetylation, H3K9ac, in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.
Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces post-translational modifications including hyperacetylation of histone 3 (H3) or histone 4 (H4) at 1,696 genes in one brain reward region [the nucleus accumbens] and deacetylation at 206 genes. At least 45 genes, shown in previous studies to be upregulated in the nucleus accumbens of mice after chronic cocaine exposure, were found to be associated with post-translational hyperacetylation of histone H3 or histone H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure.
In 2013, 22.7 million persons aged 12 or older in the United States needed treatment for an illicit drug or alcohol use problem (8.6 percent of persons aged 12 or older).