Post-Translational Modification of Proteins – MCAT Biology | MedSchoolCoach

Post-Translational Modification of Proteins

MCAT Biology - Chapter 2 - Section 1.7 - Gene Expression - The Central Dogma
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Sample MCAT Question: Post Translational Modifications

Which of the following molecules marks a protein for degradation by a proteasome?

a) Cadherin

b) Ubiquitin

c) Selectin

d) Protamine

B is correct. Ubiquitin. Ubiquitination is a form of post-translational modification that involves the addition of a ubiquitin molecule to a protein. Ubiquitin acts as a tag that marks the protein for degradation by a proteasome. Answer choice A is incorrect because it is a cell-adhesion protein. Answer choice C is an example of a glycosylated protein that is involved in cell adhesion. Answer choice D is an example of a nuclear protein.

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Post-Translational Modifications

Post-translational modifications are covalent modifications to a protein after peptide biosynthesis. Recall that ribosomes synthesize proteins by translating mRNA into polypeptide chains. After the polypeptide chains are formed, post-translational modifications will help convert them into mature protein products that can carry out their intended functions.


Post-translational modifications are covalent modifications, meaning that they involve the breaking and forming of chemical bonds. They do not involve intermolecular forces. The modifications can occur in many places on the protein, including the N-Terminus, C-Terminus, or the side chains of the amino acids. There are several types of post-translational modification, and for the MCAT exam, it is essential to know what the modifications do to the structure of the protein, as well as some common examples of how these modifications can affect protein function.


Phosphorylation is the most common type of post-translational modification, and it involves the addition of a phosphate group to a protein. There are two primary examples of the use of phosphorylation. One is for reaction coupling, and the other is to regulate enzyme activity. 

Recall that reaction coupling involves helping an energetically unfavorable, non-spontaneous reaction occur by coupling it to a more favorable reaction. One example of reaction coupling in action is the sodium-potassium pump. The sodium-potassium pump is responsible for pumping three sodium ions out of the cell and two potassium ions into the cell against their concentration gradients. This process occurs non-spontaneously. In order to make it a spontaneous one, ATP phosphorylates or adds a phosphate onto the sodium-potassium pump. Once the pump is phosphorylated, this catalyzes the exchange of sodium and potassium ions, and the reaction becomes energetically favorable.

Another example of phosphorylation is through the regulation of enzyme activity. Many enzymes exist that are inactive in the absence of a phosphate group. These enzymes only become active once they become phosphorylated. Also, some enzymes are active when they are not phosphorylated. In these cases, the addition of a phosphate group inactivates these enzymes. Both phosphorylation and dephosphorylation are fundamental mechanisms for altering enzyme activity.


Another type of post-translational modification is acetylation. Acetylation involves the addition of an acetyl group, the process of which is shown in Figure 1. In acetylation, the amino acid side chain becomes acetylated or has an acetyl group added to it. A notable example of acetylation is histone acetylation. Recall that DNA has a sugar-phosphate backbone that gives DNA a negative charge. This negatively charged DNA is wrapped around histone proteins that contain many basic amino acids that are positively charged. Acetylation of the histones and basic amino acids effectively removes the positive charges from the histone proteins. In this way, the DNA would bind less tightly to the histone proteins, making it more available for transcription. In other words, histone acetylation can increase the transcription of genes and alter gene expression.

Post-Translational Modifications - Acetylation
Figure 1. Post-Translational Modifications - Acetylation


A third type of post-translational modification that is important to know is glycosylation, which is the addition of a carbohydrate to a protein. There are two important examples of glycosylation. One example is the addition of a carbohydrate group to help a protein fold into its proper form. Another example concerns viruses. Generally, the immune system will recognize a virus by its protein code and destroy it. However, viruses are capable of covering their proteins with carbohydrates through glycosylation. This process allows them to be shielded from the immune system. It is interesting to note that some researchers assert that the 2019 novel coronavirus, although closely related to its predecessor SARS-CoV, has significant glycosylation variations at specific sites that may affect its pathogenesis.


Another example of post-translational modification is hydroxylation. Hydroxylation is the addition of a hydroxyl, or -OH, group. Hydroxylation is important for detoxification, because many toxins that are harmful to certain organisms are hydrophobic, and they cannot be excluded in solution because they do not dissolve in water. Hydroxylation, however, will oxidize these compounds, introducing a polar -OH group. When this occurs, it will allow these toxins to be dissolved in water and be excluded. In other words, hydroxylation oxidizes compounds for detoxification.


Methylation is another post-translational modification. This process involves the addition of a methyl group. Similar to acetylation, methylation of histone proteins can alter gene expression. However, histone methylation can increase or decrease gene expression. Note that this is different from DNA acetylation that increases gene expression. An important example of DNA methylation decreasing gene expression is the inactivation of one of the two X chromosomes in females. This inactivation occurs due to dosage compensation and to make sure that females are not expressing too many proteins from the X chromosome.


Ubiquitination is a post-translational modification that involves the addition of a ubiquitin molecule to a protein. The ubiquitin molecule acts as a tag that will mark the protein for degradation by the proteasome. Usually, ubiquitin serves to rid the body of damaged proteins, and it even plays a role in the immune system. However, in some cases, the ubiquitin pathway can become hyperactivated, resulting in autoimmune damage. Moreover, several diseases are implicated with disruptions in ubiquitination, such as Alzheimer’s disease, certain types of anemia, and even cancer.


Another post-translational modification is cleavage, which involves the hydrolysis of a peptide bond. Occasionally, after a peptide is synthesized, it will be cleaved into two or more pieces. Cleavage is an important process because, many times, it is required to convert proteins into their active forms. Some common examples of cleavage are prohormones and zymogens. Zymogens are inactive enzymes that, when cleaved, become active. For example, the stomach releases the inactive form of the enzyme pepsin, called pepsinogen. Pepsinogen is cleaved into its active form, pepsin, in the stomach. Pepsin is an active protease that is important for breaking down proteins for digestion.

Disulfide-Bond Formation

Disulfide-bond formation is another post-translational modification. The formation of a disulfide bond, which is a covalent modification, is important for stabilizing protein structure. Figure 2 shows an example of both disulfide-bond formation and cleavage through the formation of the hormone insulin. Insulin is translated as pre-proinsulin, which is an inactive form of insulin. Remember, insulin is a hormone that plays an important role in the regulation of glycolysis and gluconeogenesis. In terms of insulin activation, the first process to occur is the formation of disulfide-bonds in the peptide chain, creating disulfide bridges. At this point, the molecule is known as proinsulin. Next, the proinsulin molecule will undergo cleavage, in which part of the peptide chain is removed. This process results in the formation of a molecule with two separate peptide chains held together by disulfide bonds. This is mature insulin.

Post-Translational Modifications of Insulin
Figure 2. Post-Translational Modifications of Insulin

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