Post-translational modifications: what are they and how are they associated with disease?

Let's see what post-translational modifications are and what they explain about the human genome.

Proteins are the macromolecules of life. They represent 80% of the dehydrated protoplasm of the whole cell and form about 50% of the dry weight of all our tissues, so growth, biosynthesis and tissue repair depend entirely on them.

The amino acid is the basic unit of the protein, because through consecutive peptide bonds, these molecules give rise to the protein chains we know from biology lessons. Amino acids are composed of carbon (C), oxygen (O), nitrogen (N) and hydrogen (H), 4 of the 5 bioelements that make up 96% of the cell mass of the Earth. To give you an idea, we have 550 gigatons of organic carbon on the planet, 80% of which comes from the plant matter that surrounds us.

The process of protein synthesis within the cell is a complex dance between DNA, RNA, enzymes and assembly chains. In this opportunity, we give you an overview of protein formation at the cellular level, with special emphasis on post-translational modifications..

The basics of protein synthesis in the cell

First of all, we must lay certain foundations. The human being has its genetic information inside the nucleus (excluding the mitochondrial DNA), and this contains protein or RNA coding sequences, called genes. Thanks to the Human Genome Project, we know that our species has about 20,000-25,000 coding genes, which represents only 1.5% of the total DNA in our organism..

DNA is composed of nucleotides, which are of 4 types, according to their nitrogenous base: adenine (A), guanine (G), cytosine (C) and thymine (T). Each amino acid is encoded by a triplet of nucleotides, known as "codons". Here is an example of a few triplets:

GCU, GCC, GCA, GCG

All of these triplets or codons code for the amino acid alanine, interchangeably.. However, they do not come directly from genes, but are RNA segments, which are obtained from the transcription of nuclear DNA. If you know genetics, you will have noticed that one of the codons has uracil (U), the thymine (T) analog of RNA.

Thus, during transcription, a messenger RNA is formed from the information present in the genes and travels out of the nucleus to the ribosomes, which are located in the cytoplasm of the cell.. Here, the ribosomes "read" the different codons and "translate" them into chains of amino acids, which are carried one by one by the transfer RNA. Here is one more example:

GCU-UUU-UCA-CGU

Each of these 4 codons codes, respectively, for the amino acids alanine, phenylalanine, serine and arginine. This theoretical example would be a tetrapeptide (oligopeptide), since to be a protein in use, it must contain at least 100 of these amino acids. In any case, this explanation covers, in a general way, the processes of transcription and translation that give rise to proteins inside cells.

What are post-translational modifications?

Post-translational modifications (PTMs) refer to chemical changes that proteins undergo once they have been synthesized in the ribosomes.. Transcription and translation result in propeptides, which must be modified in order to ultimately achieve the actual functionality of the protein agent. These changes can take place by enzymatic or non-enzymatic mechanisms.

One of the most common post-translational modifications is the addition of a functional group. In the following list, we give you some examples of this biochemical event.

• Acylation: consists of the addition of an acyl group. The compound that donates this group is known as the "acyl group". Aspirin, for example, comes from an acylation process.
• Phosphorylation: consists of the addition of a phosphate group. Post-translational modification associated with energy transfer at the cellular level.
• Methylation: addition of a methyl group. It is an epigenetic process, since DNA methylation makes it possible to prevent the transcription of certain target genes.
• Hydroxylation: addition of a hydroxyl group (OH). The addition of the hydroxyl group to proline, for example, is an essential step in the formation of collagen in living organisms.
• Nitration: addition of a nitro group.

There are many more mechanisms of functional group addition, as nitrosylation, glycosylation, glycation or prenylation have also been reported.. From the formation of drugs to the synthesis of biological tissues, all these processes are essential for the survival of our species, in one way or another.

As mentioned above, the human genome contains 25,000 genes, but the proteome of our species (the total number of proteins expressed in a cell) is about one million protein units. In addition to the splicing of messenger RNA, post-translational modifications are the basis of protein diversity in humans, since they are able to add new proteins to the messenger RNA.They are capable of adding small molecules by means of covalent bonds that completely change the functionality of the polypeptide.

In addition to the addition of specific groups, there are also modifications that link proteins to each other. An example is sumoylation, which adds a miniature protein (small ubiquitin-related modifier, SUMO) to target proteins. Protein degradation and nuclear localization are some of the effects of this process.

Another important additive post-translational mechanism is ubiquitination which, as its name suggests, adds ubiquitin to the target protein. One of the multiple functions of this process is to direct protein recycling, since ubiquitin binds to the polypeptides to be destroyed.

To date, some 200 different post-translational modifications have been detected, which affect many aspects of protein recycling.These affect many aspects of cell functionality, including mechanisms such as metabolism, signal transduction and protein stability itself. More than 60% of the protein sections resulting from posttranslational modifications are associated with the area of the protein that interacts directly with other molecules, or in other words, its active center.

Post-translational modifications and pathological conditions

The knowledge of these mechanisms is already a treasure for society, but things get even more interesting when we discover that post-translational modifications are also useful in the medical field.

Proteins with the sequence CAAX, cysteine (C) - aliphatic residue (A) - aliphatic residue (A) - any amino acid (X), are part of many molecules with nuclear lamins, are essential in various regulatory processes, and are also present on the surface of cytoplasmic membranes (the barrier that delimits the inside of the cell from the outside). The CAAX sequence has historically been associated with the development of diseases, as it governs the post-translational modifications of the proteins that present it..

As indicated by the European Commission in the article CAAX Protein Processing in Human DIsease: From Cancer to Progeria, the enzymes that process proteins with the CAAX sequence are currently being used as therapeutic targets for cancer and progeria. The results are too complex at the molecular level to describe in this space, but the fact that post-translational modifications are being attempted as a target for study in disease highlights their clear importance.

Summary

Of all the data presented in these lines, we would like to highlight one of particular importance: human beings possess in our genome about 25,000 different genes, but the cellular proteome amounts to one million proteins.. This figure is made possible by post-translational modifications, which add functional groups and link proteins together, in order to give specificity to the macromolecule.

If we want you to keep one central idea in mind, it is this: DNA is transcribed into messenger RNA, which travels from the nucleus to the cell cytoplasm. Here, it is translated into protein (from which it harbors its instructions in the form of codons), with the help of transfer RNA and ribosomes. After this complex process, post-translational modifications take place, with the aim of giving the propeptide its final functionality.

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