In the case of cancer, the cells do not kill themselves as required, while other diseases, such as Alzheimer's, are characterized by increased apoptosis. By controlling the interactions between tBID and MTCH2, we may be able to overcome such problems
Cell suicide is a fairly routine occurrence. When a cell gets old, grows old, stops functioning, suffers irreversible damage, or when changes in its genetic material threaten to make it cancerous, a special mechanism is activated whose purpose is to end the cell's life before it causes even more serious damage to the entire body.
To commit suicide, the cell does not use external aids, but the means found within the cell itself, and the program coded in the DNA of each cell. The common suicide program - called, in scientific language, apoptosis - is done by opening the membranes that envelop important cell organelles called mitochondria. Following this, the mitochondrial proteins are released into the cell body. These proteins, which are usually harmless, join other proteins found in the cell, and together they interfere with the necessary life processes, and eventually destroy the cell.
Prof. Eitan Gross, from the Department of Biological Control at the Weizmann Institute of Science, investigates several steps in this complex process, and focuses on the proteins that transmit the suicide command to the mitochondria, and activate the necessary chain of events. In the first phase, his research dealt with a protein called BID, which is involved in the suicide pathway. Later in his research, Prof. Gross discovered that in order to activate the BID protein, it must be cut by another molecule. The cleavage product - BID for short, or tBID - activates two additional proteins - BAX and BAK. As a result of this chain of events, the outer membrane of the mitochondrion begins to leak. These leaks not only interfere with the main activity of the mitochondrion - converting nutrients into energy that drives the cell, but also release various proteins into the cell body. Some of these proteins have already been identified as players who play a role in the advanced stages of apoptosis, and it is possible that additional proteins - which have not yet been identified - are also involved later in the process.
A few years ago Prof. Gross and the members of the research group he heads identified another player, called Mitochondrial carrier (MTCH2 homolog 2). It is a new protein, which has not yet been identified or characterized, located on the outer membrane of the mitochondria.
What does this protein do? To answer the question, Prof. Gross and the members of his group - Dr. Yehudit Salzman, research student Liat Shechnai, Dr. Nathalie Yevgi-Ohana and research student Maria Marianowitz, with the help of Dr. Rebecca Hefner and the members of the Transgenic Mice Unit in the Department of Veterinary Resources - created mice that the gene coding for the MTCH2 protein was "deleted" from their entire bodies. These mice died before birth, that is which led to the conclusion that the protein plays an essential role in development. To circumvent the problem, the scientists created mice in which the gene could be deactivated in a controlled manner, in certain organs at certain times, and "deleted" the gene from the liver.
The results of the study, recently published in the scientific journal Nature Cell Biology, show that the MTCH2 protein plays the role of a receptor. It is from its location on the outer wall of the mitochondria that it makes contact with the tBID protein, and recruits it to the mitochondrion. The research findings show that when the receptor is missing, the apoptosis process is weakened. In this case, most of the tBID does not reach the mitochondria, the suicide message to BAX and BAK proteins is weakened, and the membranes are less leaky. Prof. Gross and members of his group continue to investigate MTCH2 with the aim of discovering additional roles that this protein may play. "For many proteins, apoptosis is a 'night job', while the 'day job' may be completely different, says Prof. Gross. "We hypothesize that in its 'day job', MTCH2 does not function as a receptor at all - this is because it is very similar to carrier proteins that transport various substances beyond the mitochondrial membranes. At this point we are trying to understand what it does besides its role in promoting cell suicide. Our initial findings hint at a possible interesting connection to the building and breaking down of fatty acids." The fact that apoptosis plays a necessary role in so many processes - from embryonic development to preventing the development of cancerous tumors - makes the MTCH2 protein an important drug target. Prof. Gross: "In cases of cancer , the cells do not commit suicide as required, while other diseases, such as Alzheimer's, are characterized by increased apoptosis. By controlling the interactions between tBID and MTCH2, we may be able to overcome such problems."
The "Knowledge Research and Development" company, which promotes the development of applications based on the inventions of Weizmann Institute of Science scientists, registered a patent for the protein. These days, research is being conducted in Prof. Gross's laboratory, and in other research groups, with the aim of mapping the areas of activity and the interactions of the two proteins, in order to develop new molecules that are able to block or accelerate the process in disease states.
