Post-translational modifications

Main stages of protein molecule maturation

Immediately after translation is completed, the newly synthesized polypeptide chain is merely a linear sequence of amino acids. To begin performing its biological functions, the protein undergoes a series of transformations:

• Folding. This is the process of forming the unique spatial structure of the molecule. Specialized proteins — chaperones — play a key role here. They not only help the polypeptide fold into the correct, functionally active conformation, but also prevent undesirable interactions with other molecules.
• Partial proteolysis. In many cases, the primary chain is synthesized with an "excess". Partial proteolysis consists of the enzymatic cleavage (removal) of a specific part of the polypeptide chain, which often serves as a trigger for the activation of an enzyme or hormone.
• Formation of disulfide bonds. Specific covalent cross-linking occurs between the radicals of the amino acid cysteine. These strong bridges are critically important for maintaining and stabilizing the tertiary structure of the protein.
• Addition of prosthetic groups. Some proteins require non-protein components for their function (e.g., metal ions, vitamins, or complex organic molecules). The addition of such prosthetic groups makes the protein fully functional.
• Formation of oligomeric structures. If the working protein must consist of several subunits (have a quaternary structure), their association takes place. This assembly process is also carried out with the direct participation of chaperones.

Chemical modifications of amino acid residues

In addition to changing the length of the chain and its spatial folding, protein maturation includes point chemical modifications of already incorporated amino acids. This imparts new chemical properties to the molecule and tailors it for specific functions.

The main types of such modifications include:

1. Carboxylation — addition of a carboxyl group.
2. Phosphorylation — attachment of a phosphoric acid residue (a crucial mechanism for regulating enzyme activity).
3. Iodination — incorporation of iodine atoms (characteristic of thyroid hormones).
4. Hydroxylation — attachment of a hydroxyl (-OH) group.
5. Acylation — introduction of an acyl (acid) residue.
6. Glycosylation — attachment of carbohydrate components resulting in the formation of glycoproteins.

Examples of post-translational changes: from precursor to active form

Let us examine how the characteristics of polypeptide chains change using examples of the body's most important proteins.

1. Insulin

• Immediately after translation: synthesized as a single long polypeptide chain — preproinsulin, consisting of 104 amino acid residues.
• Functionally active molecule: after partial proteolysis, it converts into a structure of two short polypeptide chains (one containing 21 and the other 30 amino acid residues). The chains are securely connected by disulfide bonds (-S-S-): there are two interchain bonds and one intrachain bond.

2. Hemoglobin A (HbA)

• Immediately after translation: two non-identical chains ($\alpha$ and $\beta$) are formed. At this stage, they contain a greater number of amino acid residues than the protomers within the "mature" erythrocyte protein.
• Functionally active molecule: represents an almost ideal spherical particle. It consists of four protomers ($2\alpha$ and $2\beta$), each of which is firmly bound to its prosthetic group — heme.

3. Tropocollagen I

• Immediately after translation: three separate chains are synthesized that are significantly longer than mature collagen polypeptide chains. They contain a large number of standard proline (Pro), lysine (Lys), and glycine (Gly) residues.
• Functionally active molecule: a classical fibrillar protein (classified as a glycoprotein) is formed. Three chains intertwine to form a strong right-handed superhelix. As a result of specific modifications (hydroxylation), the mature protein contains numerous hydroxyproline and hydroxylysine residues.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of action of chaperones and chaperonins in folding
• Enzymes catalyzing chemical modifications of amino acids
• Pathologies associated with impaired protein folding (amyloidoses, prion diseases)
• The role of vitamin C in proline hydroxylation during collagen synthesis
• The process of signal peptide cleavage during protein translocation

Other topics in the section "Template Biosyntheses"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.