6.8
Covalently Linked Protein Regulators
Many proteins are regulated by covalently linked molecules, including functional groups, such as methyl or acetyl moieties, and small proteins, such as ubiquitin.
Covalent linkages occur on specific amino acids in the polypeptide chain. For example, phosphate groups are covalently linked to serine, threonine, or tyrosine; methyl and acetyl groups are linked to lysine; and ubiquitin is linked to lysine, cysteine, serine, or threonine residues.
An enzyme or pair of enzymes reversibly catalyzes these post-translational modifications. An acetyltransferase can acetylate a protein, while a deacetylase can later remove the group.
These modifications can alter a protein’s function or localization in a cell.
For example, acetylation of histone proteins regulates gene expression by opening up the DNA structure to activate gene transcription. Methylation of histone proteins, on the other hand, is known to repress transcription by tightening the structure.
Another example is p53, a multidomain tumor suppressor protein that undergoes several covalent modifications in response to stress. Exposure to DNA damaging agents, such as UV and gamma radiation, can result in phosphorylation of the protein.
Phosphorylation improves stability and activates p53, causing it to bind to DNA damaged by the radiation and prevents cells with mutated DNA from dividing uncontrollably.
In addition to phosphorylation, different types of modifications occurring on a single protein molecule, such as p53, allow it to precisely control its functions such as cell cycle arrest, DNA repair, and apoptosis of a cell.
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein. Phosphate groups can only be covalently attached to the amino acids serine, threonine, and tyrosine, whereas methyl and acetyl groups can only be linked to lysine. These groups are added to and removed from a protein by an enzyme or pair of enzymes. For example, an acetyltransferase adds an acetyl group to a protein, and a deacetylase can remove it. Each of these modifiers can have different effects on the protein to which it is attached depending on the number and location of the modifications. When a single ubiquitin molecule is covalently linked to a certain cell surface receptor, this protein is targeted for endocytosis; on the other hand, when multiple ubiquitins linked together are attached to this protein, it is marked as a target for proteolytic degradation.
A single protein can undergo multiple modifications simultaneously to control its function. One well-known example of a protein regulated by multiple covalent modifications is the tumor-suppressor protein, p53. p53 undergoes a variety of modifications in response to various types of stress, including radiation and carcinogens. Some modifications include phosphorylation, acetylation, and sumoylation in response to UV and gamma radiations. The sites and types of modifications can vary depending on the stressor. Studies have shown that UV and gamma radiation can result in the phosphorylation of serine 33, but serine 392 can be phosphorylated when exposed to UV but not gamma radiation. Other kinds of stress, such as exposure to hypoxia, anti‐metabolites, and actinomycin D, can result in the acetylation of p53. The modifications can also vary between different cell types and organisms.
Many proteins are regulated by covalently linked molecules, including functional groups, such as methyl or acetyl moieties, and small proteins, such as ubiquitin.
Covalent linkages occur on specific amino acids in the polypeptide chain. For example, phosphate groups are covalently linked to serine, threonine, or tyrosine; methyl and acetyl groups are linked to lysine; and ubiquitin is linked to lysine, cysteine, serine, or threonine residues.
An enzyme or pair of enzymes reversibly catalyzes these post-translational modifications. An acetyltransferase can acetylate a protein, while a deacetylase can later remove the group.
These modifications can alter a protein’s function or localization in a cell.
For example, acetylation of histone proteins regulates gene expression by opening up the DNA structure to activate gene transcription. Methylation of histone proteins, on the other hand, is known to repress transcription by tightening the structure.
Another example is p53, a multidomain tumor suppressor protein that undergoes several covalent modifications in response to stress. Exposure to DNA damaging agents, such as UV and gamma radiation, can result in phosphorylation of the protein.
Phosphorylation improves stability and activates p53, causing it to bind to DNA damaged by the radiation and prevents cells with mutated DNA from dividing uncontrollably.
In addition to phosphorylation, different types of modifications occurring on a single protein molecule, such as p53, allow it to precisely control its functions such as cell cycle arrest, DNA repair, and apoptosis of a cell.
- Post-Translational Modification - Covalent modifications made to proteins after synthesis.
- Covalently Linked Proteins - Proteins that have been chemically bonded together.
- Protein Degradation - The process by which proteins are broken down in cells.
- Covalent Regulation - Control of protein function by adding/removing chemical groups.
- Ubiquitination - A post-translational modification involving the attachment of ubiquitin to proteins.
- Define Post-Translational Modification - The changes made to proteins after they are synthesized (e.g., covalently linked).
- Contrast Pre and Post-Translational Modification - Understand the differences and unique functions (e.g., covalent regulation vs ubiquitination).
- Explore Examples - How proteins are targeted for degradation (e.g., ubiquitination).
- Explain the Process - How post-translational modifications regulate protein functions.
- Apply in Context - How post-translational modifications impact biological systems.
- What is Post-Translational Modification and why is it important?
- What are the different types of Post-Translational Modifications?
- How does Post-Translational Modification regulate protein function?
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