Prof. Mark Sapro and members of his research group, Dr. Nina Moore and Dr. Liron Klipzan, from the Department of Structural Biology, recently showed how one of the most common substitutions of amino acids manages to escape the molecular radar, whose job it is to prevent such mistakes. The findings may be relevant to Alzheimer's disease.
Considering the fact that our body has tens of thousands of different proteins, built from amino acid chains of thousands of units, we can say that the rate of errors is very low. And yet, every now and then, a piece of foreign material infiltrates the production line of the protein factory in the ribosome, and enters the amino acid chain. Since the sequence of amino acids determines its folded three-dimensional shape and its function, a single broken link is sometimes enough to cause disaster.
Prof. Mark Sapro And the members of his research group, Dr. Nina Moore and Dr. Liron Klipzan, from the Department of Structural Biology, recently showed how one of the most common substitutions of amino acids manages to escape the molecular radar, whose job it is to prevent such mistakes. The findings may be relevant to Alzheimer's disease.
Prof. Speru and the research group he heads are investigating a key step in the complex process of protein production. At this stage, "quality control" is carried out in order to make sure that the translation of the final protein is indeed done exactly according to the instructions found in the RNA. This is done in cooperation between an adapter RNA molecule called transfer RNA, and a certain enzyme (amino acyl T-RNA synthetase). If we think of the RNA transporter as a "truck" that takes the amino acid units to the production line in the ribosome, the enzyme is a "bearer" that loads the amino acids onto the trucks. Each "sorcerer" knows one amino acid, which he grabs and loads. Some of the porters have an additional responsibility: since some of the amino acids are similar to each other, and may cause confusion, the porters also function as quality controllers, who check the goods once more before shipping.
Such is the situation, for example, in the case of the amino acid tyrosine, the difference between it and another amino acid, phenylalanine, comes down to the addition of only two atoms - oxygen and hydrogen. In the case of tyrosine there is another complication, because it can be confused with another molecule, which is similar to an amino acid, but has a completely different function. This molecule is called L-Dopa, and it is recognized as a cure for Parkinson's disease. Al-dopa's similarity to tyrosine is no accident: this molecule is created naturally in the body by adding oxygen and hydrogen to the amino acid tyrosine. The simulated amino acid is then able to enter the brain, where it is converted into dopamine - the neurotransmitter missing in Parkinson's patients. But, when Al-Dopa "impersonates" tyrosine and mistakenly enters a protein, the extra atoms cause problems. The tiny supplement has a chemical activity that causes the accumulation of proteins, which leads to the formation of protein clumps that do not break down easily.
Prof. Safro and his colleagues realized that in fact the question of Al-Dopa's penetration into proteins is even more complicated, since there are two types of enzyme-passengers: one is found in the cytoplasm of the cell, and the other in the mitochondria - the power plants that produce the energy in the cell. The scientists created crystals of both types, and explained their spatial structure. They discovered that the enzyme found in the mitochondria is smaller and simpler than the version found in the cytoplasm. Among other things, he lacks the necessary equipment for "quality control".
In the next experiment, they wanted to check to what extent each of the two versions of the enzyme is able to recognize Al-Dopa, and prevent it from penetrating into the protein chain. The scientists used a variety of experimental methods - including kinetic measurements and protein synthesis, through which they even managed to capture the three-dimensional structure of the enzyme and al-Dopa during their joint activity - and showed how the mistake occurs. "Probably in this specific case, the quality control mechanism is not able to deliver the goods," says Prof. Sapro. "Al-Dopa is located inside the enzyme in a similar way to the amino acid, and the quality control equipment is unable to detect it." The failure to recognize al-dopa occurred in both versions of the enzyme, but was particularly prominent in the mitochondrial enzymes. Unfortunately, these enzymes have a greater impact on human health.
Errors in protein production are rare. Allegedly, Al-Dopa is a rare and unique case of poor identification, but it may also be critical: protein clumps such as those formed by the mistaken penetration of Al-Dopa into protein chains are involved in Alzheimer's disease, and Prof. Sparrow believes that this "blind spot" in the quality control mechanism may contribute to the development of the disease.
