10.10:
Regulated Protein Degradation
Cells need to regulate their levels of intracellular proteins according to the alterations in their state, such as environmental stimuli, or other metabolic or developmental changes.
This regulation or control of protein concentrations inside a cell depends on their rate of synthesis as well as their degradation.
In eukaryotes, intracellular protein degradation is mostly mediated by the ubiquitin-proteasome system. This system serves two primary functions inside the cells – the quality control of misfolded or damaged proteins, and the control of the levels of important cellular proteins.
The specificity of the proteasomal degradation in the cell is regulated through various mechanisms.
Eukaryotic cells have a class of proteins called E3 ligases – the main catalytic unit of ubiquitin ligase. Each of these unique E3 molecules can ubiquitinate only a specific target protein upon activation.
Each E3 protein ligase can also only be activated through a specific signal such as phosphorylation, allosteric transition due to ligand binding, or protein subunit addition. This regulates the ubiquitination of the target protein leading to its degradation by the proteasome.
For example, APC, or anaphase-promoting complex, is a multi-subunit E3 ligase responsible for the degradation of important cell cycle regulators. However, it is only activated at specific time points during the cell cycle by the addition of co-activator subunits. These subunits play an important role in the selective binding of the APC to its target proteins.
Alternatively, a conformational change in the target protein itself upon phosphorylation of a specific site, or dissociation of a protein subunit, or cleavage of a peptide bond, can unmask a normally hidden degradation signal. This signal can then be recognized by a ubiquitin ligase, resulting in the protein’s ubiquitination.
For example, cyclin proteins contain an internal degradation signal which can only be recognized by APC. However, this signal is only exposed when a cyclin kinase phosphorylates a specific site in the cyclin protein. This brings about a conformational change in the protein that unmasks its degradation signal – leading to its polyubiquitinylation, and degradation in the proteasome.
10.10:
Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a diseased state. It also aids in controlling the levels of otherwise healthy proteins, which only have a short-lived function inside the cell under certain conditions.
One of the major protein degradation pathways active in eukaryotic cells is the ubiquitin-proteasome pathway. However, even this pathway is tightly regulated to only allow degradation of specific target proteins under certain conditions. Two of the most common regulatory mechanisms are the tight control of E3 ubiquitin ligase activity, and the unmasking degradation signals in the target proteins.
Humans have an estimated 600 or more E3 ubiquitin ligase genes, each of which can mediate their own target proteins' ubiquitination. However, E3 ligase activity is regulated via different mechanisms of action such as phosphorylation, or ligand binding. Similarly, the unmasking of degradation signals in the intracellular proteins is controlled by several different mechanisms such as phosphorylation, peptide bond cleavage, or protein subunit dissociation. Only when the E3 ligases recognize these normally hidden degradation signals can the target protein be ubiquitinated and degraded by the proteasome.
Suggested Reading
- Regulated Protein Degradation. Trends in Biochemical Sciences. Vol 30, Issue 6, 283-286, 2005.
- Protein Degradation and the Pathologic Basis of Disease. The American Journal of Pathology. Vol 189, Issue 1, 2019, 94-103