Why are there two mechanisms for breaking down proteins in the body?
Tiny "pairs of scissors" circulate in the cells of our body: these are tiny molecular machines that move in most parts of the cell and break down unwanted proteins. Weizmann Institute of Science scientists discovered a control mechanism that controls these molecular "scissors". Their findings, recently published in the scientific journal Nature Communications, may help in the development of anti-cancer drugs that will cause fewer side effects, and point to new directions for the study of Parkinson's disease.
The elimination of unwanted proteins - those that have been worn, damaged, or are simply no longer needed - is an essential process for the functioning of the organism, so important that two different mechanisms responsible for its execution have evolved. The more well-known and studied mechanism is activated by a large molecular cluster called "proteasome", which recycles proteins marked for degradation. The second mechanism, which was discovered at a later stage, is the molecular scissors: this is a reduced proteasome molecule, which includes only the part necessary for cutting proteins. These "scissors" do not wait until the unwanted proteins are marked, but immediately disassemble proteins that lack a XNUMXD folded structure.
Despite their inherent usefulness, such pairs of scissors, which rotate freely and cut into pieces all the unfolded proteins, can also create problems. The lack of folding of a protein may indicate damage, so it makes sense to eliminate the damaged proteins without wasting time on marking them. Indeed, the same cutting proteasome works mainly in emergency situations called "oxidative stress", in which a lot of damage is caused to the proteins in the cell. But recently it was discovered that almost half of all normal proteins in the cell also include non-folded segments; For example, the protein p53 - one of the main defenders of the cell against cancer. In addition, in the cell there are many unstructured proteins that perform other key functions, such as control of cell division or control of gene expression. Therefore, in order for the degradation to take place only if necessary, control mechanisms responsible for the cutting proteasome are necessary.
One of these control mechanisms has now been identified by Dr. Michal Sharon and her group members in the Institute's Department of Biological Chemistry: Dr. Oren Moskovitz, Dr. Gili Ben-Nisan, Irit Feiner, Dan Polak and Limor Mizrahi. The scientists found that the protein called DJ-1 inhibits the activity of the cutting proteasome, thus slowing down the breakdown of the unstructured proteins. The study showed, for example, that DJ-1 prevents these molecular "scissors" from cutting the p53 protein into pieces. In addition, the scientists showed that DJ-1 attaches directly to the cutting proteasome - thereby inhibiting its activity.
Deciphering the mechanisms of protein degradation in depth may, in the future, help to control this process more precisely. For example, several innovative anti-cancer drugs prevent the proteasome from breaking down anti-cancer proteins, but they also prevent the breakdown of many other proteins, thereby causing side effects. A deeper understanding of the decomposition process, resulting from the new research, may in the future help in the development of drugs that prevent the decomposition in a more precise way.
Furthermore, the study may shed new light on Parkinson's disease. Recently, studies were carried out that showed that mutations in the gene coding for DJ-1 cause a hereditary version of this disease, which breaks out at a young age. The research carried out at the institute indicates the possible involvement of the DJ-1 protein in Parkinson's disease, and these findings may point to new directions for researching the mechanisms of the disease.
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