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

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 of our tissues, so tissue growth, biosynthesis and repair are completely dependent 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 that we know from biology lessons. Amino acids are made up of carbon (C), oxygen (O), nitrogen (N) and Hydrogen (H), 4 of the 5 bioelements that make up 96% of the Earth's cell mass. 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 will tell you some general brushstrokes of the formation of proteins at the cellular level, with special emphasis on post-translational modifications.

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The Basis of Protein Synthesis in the Cell

First of all, we must lay certain foundations. The human being has its genetic information within the nucleus (not counting the mitochondrial DNA), and this has some coding sequences for proteins or RNA, called genes. Thanks to the Human Genome project, we know that our species has some 20,000-25,000 coding genes, which only represents 1.5% of the total DNA in our body.

DNA is composed of nucleotides, which are of 4 types, according to the nitrogen base they present: adenine (A), guanine (G), cytosine (C) and thymine (T). Each amino acid is encoded by a triplet of nucleotides, which are known as "codons." We give you the example of a few triplets:

GCU, GCC, GCA, GCG

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

So that, During transcription, a messenger RNA is formed from the information present in the genes and it travels outside 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. We give you one more example:

GCU-UUU-UCA-CGU

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

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What are post-translational modifications?

Post-translational modifications (PTM) refer to the chemical changes that proteins undergo once they have been synthesized in ribosomes. Transcription and translation give rise to propeptides, which must be modified to ultimately achieve the true functionality of the protein agent. These changes can take place through 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 "acylating group." Aspirin, for example, comes from an acylation process.
• Phosphorylation: consists of the addition of a phosphate group. It is the post-translational modification that is associated with the transfer of energy at the cellular level.
• Methylation: add a methyl group. It is an epigenetic process, since DNA methylation prevents 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 for the formation of collagen in living beings.
• Nitration: addition of a nitro group.

There are many more mechanisms for adding functional groups, since nitrosylation, glycosylation, glycation or prenylation have also been recorded.. 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 we have said before, the human genome contains 25,000 genes, but the proteome of our species (the total of proteins expressed in a cell) is around one million protein units. In addition to the splicing of messenger RNA, post-translational modifications are the basis of protein diversity in humans, as they are capable of adding small molecules through 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 together. An example of this 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 polypeptides that must be destroyed.

Today, some 200 different post-translational modifications have been detected, which affect many aspects of cellular functionality, among which are mechanisms such as metabolism, signal transduction and protein stability itself. More than 60% of the protein sections resulting from post-translational modifications are associated with area of ​​the protein that interacts directly with other molecules, or what is the same, its center active.

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Post-translational modifications and pathological pictures

Knowledge of these mechanisms is in itself a treasure for society, but things get even more interesting when we discovered that post-translational modifications also have utility in the field doctor.

Proteins that have within them the sequence CAAX, cysteine ​​(C) - aliphatic residue (A) - aliphatic residue (A) - any amino acid (X), are part of many molecules with nuclear laminae, are essential in various regulatory processes and, in addition, They are also present on the surface of cytoplasmic membranes (the barrier that delimits the interior of the cell of the Exterior). The CAAX sequence has historically been associated with the development of diseases, since 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, today is trying to use as therapeutic targets for cancer and progeria the enzymes that process proteins with the sequence CAAX. The results are too complex at the molecular level to describe in this space, but the fact that they are The use of post-translational modifications as an object of study in diseases shows its clear importance.

Resume

Of all the data presented in these lines, we want to highlight one of special importance: Human beings have about 25,000 different genes in our genome, but the cellular proteome amounts to a million proteins. This figure is possible thanks to post-translational modifications, which add functional groups and link proteins between them, in order to give specificity to the macromolecule.

If we want you to keep a central idea, this is the following: DNA is transcribed into messenger RNA, which travels from the nucleus to the cell cytoplasm. Here, it is translated into the protein (from which it houses its instructions in the form of codons), with the help of transfer RNA and ribosomes. After this complex process, post-translational modifications take place, in order to give the protopeptide its definitive functionality.

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