Weizmann Institute of Science scientists have discovered a new cellular mechanism for identifying proteins whose 3D structure has been unraveled, thereby revealing a targeted target for cancer treatment
"Who will guard the guards?" wondered the Roman poet Juvenalis of the first century AD, but nature required this issue long before him. In our body there are proteins whose job is to protect against cancerous tumors. Like most proteins, in order to do their job faithfully, these "guardians" must fold into a meticulous three-dimensional structure, and for this they often need a helping hand. Those who guard the guards, then, are companion proteins (Chaperones) - molecules whose role is to help proteins fold into the three-dimensional structure necessary to perform their function.
Sometimes, a genetic change (mutation) in the "guardian" proteins may turn them from cancer suppressors into carcinogens. The accompanying proteins that guard them, have difficulty noticing the change and provide them with the same assistance that is provided to normal proteins. In a new study, Dr Rina Rosenzweig and her research group at the Weizmann Institute of Science, cracked the mechanism of action of a chaperone protein that "guards" a protein with a cancerous mutation. Their findings are published in the scientific journal Molecular cells, An infrastructure is laid for the development of targeted cancer treatment.
One of the most common families of chaperone proteins is JDPs, and in recent decades it has become clear that this is a large family with about 50 different representatives in humans. These chaperones are responsible, among other things, for identifying proteins whose 53D structure has unraveled or not arranged correctly and send them to reorganize with the help of other chaperone proteins. Representatives of this family help, among other things, in the folding of the protein pXNUMX known as "the guardian of the genome".
The keeper of the genome
The genome guard is a protein that in its normal form suppresses cancerous tumors, but small genetic changes that replace one of the amino acids that make it up can make it cancerous. Previous studies have shown that those who guard the "guardian of the genome" - i.e. the accompanying proteins - provide protection not only to the protein in its normal form but also to its cancerous version. The companion proteins stabilize the unstable structure of the cancerous proteins and prevent them from sticking to each other and creating messy protein aggregates, which the cell could recognize and break down without that help.
Thus, on the face of it, the chaperone proteins are a good target for the development of new cancer treatments. However, since they help a wide range of proteins in the cell, damage to them can cause serious secondary damage. The team of researchers from Dr. Rosenzweig's laboratory in the Department of Structural and Chemical Biology at the Institute, led by Dr. Guy Soltzman And in collaboration with Miri Kucharsky and Dr. Ofra Faust, he hypothesized that focusing on representatives of the JDPs family that provide assistance to the cancerous version of p53, may reveal a new target for targeted cancer treatment.
In the first step, the researchers looked at exactly which family members help p53 from cancer. To this end, they examined four groups of proteins from the JDPs family that were previously documented as affecting the progression of cancer. These experiments revealed that only companion proteins from group A help p53 from cancer, and in particular the protein DNAJA2. These findings were also verified in cancer cells, through a research collaboration with Prof. Bokau's laboratory at the German National Cancer Research Center in Heidelberg (DKFZ). But how does DNAJA2 actually manage to recognize the cancerous p53 protein and protect it?
Using advanced nuclear magnetic resonance (NMR) experiments performed at the Klor Institute for Imaging and Spectroscopy, the team of researchers was able to crack the mechanism of action of DNAJA2 and revealed a previously unknown mode of action. Most of the proteins in the cell are produced as molecular chains that fold into a three-dimensional structure so that the water-loving components are found on the outside facing the aqueous environment of the cell, while the water-repellent components are packed in the interior of the protein. Usually chaperone proteins recognize a protein that has not folded or lost its proper 2D structure by identifying exposed hydrophobic regions on the surface of the protein. "Unlike the other accompanying proteins, DNAJA53 connects to pXNUMX when it is almost completely folded," explains Dr. Rosenzweig. "It turns out that it is able to identify proteins whose XNUMXD structure has just begun to unravel - long before entire internal regions are exposed."
The NMR method allowed the scientists to follow at the atomic level the meeting between DNAJA2 and the p53 protein. This observation revealed that regions that bend like a hairpin (β-hairpin) in the chaperone protein bind to accordion-like regions (β-sheet) in the target protein. The structure of these accordion surfaces is held by hydrogen bonds, which remain stable throughout the functional life of the protein. However, when these bonds are loosened - as happens in the cancerous version of the 'guardian of the genome' - they put the protein at risk of sticking to other proteins. This is where the hairpin regions come into play, binding to these surfaces, stabilizing them and allowing the rebuilding of the hydrogen bonds. This protection given to the cancerous protein prevents the cell from recognizing and breaking it down.
When the recipe for the "headpin" was deleted from the genetic code of the companion protein, the researchers discovered that the activity of the companion protein was not affected and the damage remained focused on proteins that are particularly rich in "accordions", such as p53. "From the targeted activity of the 'hair pin', it appears that there is a possibility of developing targeted treatments for cancer using accompanying proteins, without significant damage to the normal functioning of the cells in the body," says Dr. Rosenzweig. "Our research even sets a potential target for the development of such a treatment that would impair the cancer-supporting activity of DNAJA2."
T Lu Dang, Dr. Ann S. also participated in the study. Wentink and Prof. Bernd Bockau from the German National Cancer Research Center (DKFZ), in the city of Heidelberg; Dr. Mikal Silva and Dr. Tal Ilani from the department of structural and chemical biology at the institute.
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