FQA

What is Ubiquitination?

Proteins are inactivated by the attachment of ubiquitin to them, a process called ubiquitination. Ubiquitin acts as a tag by which the protein-transport machinery ferries a protein to the proteasome for degradation.
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What is the ubiquitin function?

Ub functions to regulate protein turnover in a cell by closely regulating the degradation of specific proteins. By regulating protein degradation, cells can quickly eliminate a protein that in turn regulates another function.

What is Ubiquitin-Proteasome System (UPS)?

Ubiquitin-proteasome system (UPS) represents a major system controlling many cellular processes including DNA repair, embryogenesis, the regulation of transcription, and apoptosis. UPS process in most cases needs three types of enzymes.

1. E1 enzymes known as Ub-activating enzymes. These enzymes modify Ub so that it is in a reactive state (making it likely that the C-terminal glycine on Ub will react with the lysine side-chains on the substrate protein).
2. E2 enzymes known as Ub-conjugating enzymes. These enzymes actually catalyze the attachment of Ub to the substrate protein.
3. E3 enzymes known as Ub-ligases. E3’s usually function in concert with E2 enzymes, but they are thought to play a role in recognizing the substrate protein.

In yeast, there are many types of E1, E2, and E3 enzymes. For example, 13 different E2 enzymes have been found. While they all carry out the conjugation reaction, they are apparently tailored for specific functions. For example, Ubc2 is an E2 enzyme that works in DNA repair, while Ubc3 is also an E2 enzyme that functions to degrade cyclin as part of the cell-cycle.

How do the enzymes work?

First, Ub is activated by E1 in an ATP-dependent fashion. E2 and E3 then work together to recognize the substrate protein and conjugate Ub to it. Ub can be attached as a monomer or as a previously synthesized chain. Then, the ubiqinated protein is shuttled to the proteasome for degradation.

What are the degradation signals?

What determines if a protein gets tagged by Ub and thus marked for degradation? This question cannot yet be fully answered, but scientists have uncovered some interesting clues. Apparently, proteins can contain some form of signal that is recognized by the Ub machinery.

1. The N-degron. There is a correlation between the half-life of a protein and its N-terminal residue.
2. Certain amino acid sequences appear to be signals for degradation, such as the PEST sequence because short stretch of about eight amino acids is enriched with proline, glutamic acid, serine, and threonine. An example is the transcription factor Gcn4p. This protein is 281 amino acids in length and the PEST sequence is found at positions 91-106. The normal half-life of this protein is about 5 minutes. But if the PEST sequence is removed, the half-life increases to 50 minutes.
3. Some signals may also be subject to masking. A signal could be hidden if it is part of a protein-protein interaction. Or it may be masked by covalently attaching phosphate groups to the side chains of certain amino acids. Both of these mechanisms would thus allow for better control, as a proteins degradation signal need only be unmasked to target it for degradation. Such reversible masking appears to be involved in the regulation of both transcription factor and cyclin concentrations.
4. Signals may also be buried in the hydrophobic core. This is why partially folded or abnormal, mutant proteins may be prone to degradation.

How does ubiquitination lead to protein degradation?

The proteasome is the structure that actually does the degrading. Ubiquiton’s degradation role may simply be to decrease the rate of dissociation between proteasomes and interacting substrate proteins. Without Ub, proteins may interact with the proteasome, but quickly dissociate. Ub slows down this dissociation. A substrate protein that is conjugated with Ub-chains is thought to interact with a proteasome for a longer period of time, thus increasing the likelihood that the proteasome will degrade it. In fact, Ub could actually function to tether the substrate protein to the proteasome.

What Diseases may be associated with malfunction of UPS?

1. Cancers
2. Parkinson’s disease
3. Inflammatory diseases
4. Muscle atrophy-related diseases

What is the Example of New Drugs Developed through UPS?

Bortezimib, treatment of myeloma, FDA approved.

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