The UPS System and Why Its Discovery Won the Nobel
By Ritik Ravichandran | 1 October 2024
Everything in our body is run by proteins. They are the workforce for all processes occurring in our body. That being said, every so often, it is possible that some of these proteins misfold. This results in them becoming harmful and potentially disease causing.
Luckily , our body has developed checks for this sort of misfolding . One of these mechanisms is Targeted Protein Degradation (TPD for short). The way our body carries out this process is extremely intriguing.
There are large, barrel shaped molecules in our body known as proteosomes whose function is to break down proteins. But the question arises, if all our internal processes are facilitated by proteins, how do the proteosomes know which ones to break down and which ones to ignore? They do so with the help of a chemical tag that they recognise. The name of this molecule is ubiquitin, which is another protein (a rather ubiquitous one - hence the name) that is virtually indistinguishable across all life forms.
The actual process, however is a tad more complicated, involving three enzymes. First, ubiquitin is activated by being attached to the ubiquitin-activating enzyme, E1. The ubiquitin is then transferred to a second enzyme, called ubiquitin-conjugating enzyme (E2). The final transfer of ubiquitin to the target protein is then mediated by a third enzyme, called ubiquitin ligase or E3. It is after this that the protein is recognised by the proteasome and hence degraded. This is known as the Ubiquitin-Proteasome System (UPS), and the Nobel Prize in Chemistry in 2004 was awarded jointly to Aaron Ciechanover, Avram Hershko and Irwin Rose for the discovery of ubiquitin-mediated protein degradation.
But why was this discovery that important? To answer this, its important to look at the history of protein degradation research. A number of simple protein-degrading enzymes were already known. One example is trypsin, which in the small intestine breaks down proteins in our food to amino acids. Likewise, a type of cell organelle, the lysosome, in which proteins absorbed from outside are broken down, had long been studied. Common to these processes is that they do not require energy in order to function.
Experiments as long ago as the 1950s showed, however, that the breakdown of the cell’s own proteins does require energy. This long puzzled researchers, and it is precisely this paradox, or rather its explanation that won the 2004 Nobel Prize in Chemistry: that the breakdown of proteins within the cell requires energy while other protein degradation takes place without added energy as illustrated earlier.
This discovery hence paved the way for a novel drug delivery system that goes by the name of PROTAC (Proteolysis Targeting Chimera). This is a synthetic molecule that not only quickens the transfer of ubquitin to the target protein but also makes it more efficient. But how does it do it?
The PROTAC molecule is heterobifunctional, which is a fancy word for having two sticky sites. One of these sites binds to the E3 enzyme and the other to the target protein. It then facilitates the ubiquitylation of the protein, and hence after the formation of the ubiquitin-protein complex the PROTAC is recycled to target another copy of the target protein eventually leading to its destruction.
This discovery was groundbreaking in the field of pharmacology and medicine. Until its discovery, the way misfolded proteins would be destroyed was through the plugging of the active sites of these proteins (site in the protein that binds with other molecules), with a drug of a particular shape, thus rendering the misfolded protein incapable of harm. However, this meant that there would need to be a high concentration of the drug within the system for it to carry out its function. With PROTAC, there is a lesser amount of drug required, as PROTACs can be used in multiple cycles of degradation, which means they can maintain activity and don't need to be administered at high concentrations.
In short, PROTACs and the ubiquitin-proteasome system (UPS) make a powerful combination for targeted protein degradation. This approach can lead to more effective cancer treatments and exciting advances in personalized medicine!
References:
- Park, J., Cho, J., & Song, E. J. (2020). Ubiquitin-proteasome system (UPS) as a target for anticancer treatment. Archives of pharmacal research, 43(11), 1144–1161.
- Olguín H. C. (2022). The Gentle Side of the UPS: Ubiquitin-Proteasome System and the Regulation of the Myogenic Program. Frontiers in cell and developmental biology, 9, 821839.
- Kresge, Nicole & Simoni, Robert & Hill, Robert. (2006). The Discovery of Ubiquitin-mediated Proteolysis by Aaron Ciechanover, Avram Hershko, and Irwin Rose. The Journal of biological chemistry. 281. e32.
- Images: LifeSensors and Pinterest