Cells use proteins for everything from structural ‘bricks and mortar’ to making and receiving signals to enzymes that catalyze all of the reactions required for a cell to survive. Cells also need specialized proteins to dispose of other proteins that have broken down or are no longer needed or never quite worked correctly. Protein ‘quality control’ in the cell is not only about making the right protein at the right time in the right amount; it is also about targeting specific proteins for degradation. One of the key complexes in the cell for degrading proteins is known as the proteasome.
Structure of the Proteasome
The proteasome is a protein degrading complex consisting of multiple subunits. The proteasome core is the portion responsible for degrading proteins targeted to this degradative pathway. There are several different cleavage activities in this complex structure including trypsin-like and chymotrypsin-like. Proteins that enter the proteasome are broken down into much smaller peptide fragments that are typically only a few amino acids in length. These small peptides exit the proteasome and are degraded by other proteases in the cell.
Targeting Proteins to the Proteasome
Proteins destined for degradation by the proteasome do not find their way there by chance; they are given a specific address label. This label is a small modifier protein known as ubiquitin. If a protein needs to be sent to the proteasome it is tagged by the enzymatic addition of chains of ubiquitin molecules. The poly-ubiquitin chains are added to the target protein through the work of three important classes of proteins. E1 ubiquitin activating proteins, E2 ubiquitin conjugating proteins, and finally E3 ubiquitin protein ligases which link the ubiquitin molecules to the protein targeted for degradation.
Which Proteins Are Degraded by the Proteasome
Proteasomal degradation is utilized by cells for the removal of a number of proteins that have fulfilled their function and are ready to be recycled. Recent experimental studies have shown that the ubiquitin-proteasome pathway is also important in helping a cell deal with issues related to protein quality control. All proteins need to fold into the correct form in order to work properly, if they do not they are not only not performing their assigned function but they can also cause other problems for the cell. Because of this, cells have developed a system for eliminating incorrectly folded or “denatured” proteins known as the “unfolded protein response”. This system is vital to the cell maintaining optimal protein homeostasis and the proteasome plays a key role in it.
The importance of the ubiquitin-proteasome pathway in normal cellular and overall health has become more apparent with the finding that a mutation in one of the cell’s E3 ubiquitin ligase genes leads to the occurrence of a form of Parkinson’s disease that strikes its victims at a very young age. Additionally, this pathway has recently been targeted by a new class of drug, such as Velcade (bortezomib), as a treatment for multiple myeloma and mantle cell lymphoma.
 |
