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Proteins are also allowed to make mistakes

Where and when do mistakes happen in the production of proteins in the cell?

cell division (mitosis). Illustration from PIXABAY.COM
cell division (mitosis). Illustration from PIXABAY.COM

An American researcher once announced that he would invite to lunch - for a whole year - any scientist who could find out where and when mistakes happen in the production of proteins in the cell. Prof. Tzachi Flafel, head of the Department of Molecular Genetics at the Weizmann Institute of Science, will not be able to benefit from the invitation, due to the geographical distance, but when one of his studies was recently published in the scientific journal Molecular Cell, he sent a message to that researcher: mission accomplished.

Prof. Pepper and his research partners were not only able to measure the rate at which errors occur in the production of proteins in the cell, they also discovered that the genetic code contains a sort of "error code" that determines where errors must be avoided at all costs, and where they are tolerated or even desirable. There are mistakes, for example, that can cause proteins to accumulate in the cell, as happens in Alzheimer's disease. Conversely, certain mistakes may give a cell an evolutionary advantage.

Sometimes the source of the error is a "spelling error" in the DNA, but much more common are the errors that occur in the production process itself, when the genetic message is copied and sent to the ribosome - the factory of the cell where the proteins are assembled from their building blocks (the amino acids). Mapping these mistakes has so far been considered almost impossible, since the existing methods yield information at the cell level - and not at the level of resolution of a single amino acid; This information may indeed indicate the existence of errors in general, but not the location of the incorrect amino acids.

From the right: Dr. Roni Rek, Omar Asraf, Dr. Orna Dahan and Prof. Tzachi Falfel. Not immune to mistakes. Photo: Weizmann Institute Spokesperson
From the right: Dr. Roni Rek, Omar Asraf, Dr. Orna Dahan and Prof. Tzachi Falfel. Not immune to mistakes. Photo: Weizmann Institute Spokesperson

In collaboration with Prof. Tamar Giger from Tel Aviv University and Prof. Ariel Lindner from Paris Descartes University, Prof. Pepper faced the "impossible" task, using an innovative version of mass spectrometry that was recently developed for a different purpose: the study of acid metabolism individual amino acids in a protein. The scientists analyzed the data obtained using this method, from rapidly dividing yeast and bacterial cells, using advanced algorithms. The result: the researchers were able to discover and analyze all the mistakes that occur in the production of proteins in the cell at the resolution of a single amino acid. The research was carried out by Ernst Mordart, Prof. Pepper's PhD student. The research group also included Dr. Orna Dahan, Omer Asraf, Dr. Roni Rak and Abia Yehondav, from the department of molecular genetics at the institute, Dr. Georgina Barnabas from Tel Aviv University and Prof. Jürgen Cox from the Max Planck Institute for Biochemistry.

The research revealed that the most common mistakes happen in the ribosome, that is, in the last stage of protein production known as "translation". About one out of about 1,000 amino acids inserted into the protein at this stage is incorrect - that is, almost every protein will contain an average of one error. However, the rate of errors is not uniform and may range from one error to several tens of amino acids and from one error to several tens of thousands.

The most surprising finding was that the frequency of errors is not accidental: it is much smaller in proteins expressed in the cell in large quantities. The reason probably lies in the fact that errors in the proteins produced in large quantities would have caused them to accumulate in the cell, so that it would not have survived during evolution. Furthermore, the errors in the translation of a particular protein are much more frequent in locations that are not essential for the protein's function and stability compared to more essential locations. For example, those responsible for binding to other molecules. "We found that it is 'permissible' to make mistakes in places where the mistake is expected to cause minimal damage, but not in more sensitive places," says Prof. Pepper.

A low dose of antibiotics (at the bottom of the table) led to more errors in translation, especially in certain locations. The laboratory of Prof. Yitzhak Flafel, Weizmann Institute
A low dose of antibiotics (at the bottom of the table) led to more errors in translation, especially in certain locations. The laboratory of Prof. Yitzhak Flafel, Weizmann Institute

A low dose of antibiotics (at the bottom of the table) led to more errors in translation, especially in certain locations

But how does the ribosome know when it is "allowed" to make mistakes? The research findings indicate that the frequency of errors is pre-programmed, at least partially, through control of the translation rate. In fact, the scientists found that there is a direct relationship between the rate of translation and the number of errors: the faster the ribosome produces proteins, the greater the number of errors. In contrast, the ribosome appears to be programmed to slow down when accuracy is essential. It is possible that the rate of translation is controlled by a genetic mechanism, which was discovered in Prof. Pepper's previous studies. This mechanism is based on the fact that the same amino acid can be encoded using sequences of three different genetic letters. Some sequences allow the ribosome to speed up because they require available molecules, while others require rarer molecules, so the ribosome is forced to slow down.

In the new study, the scientists showed that external conditions can also cause errors: when the cells under study were exposed to antibiotics, the rate of errors increased.

These discoveries open up new directions of research. In future studies it will be possible to test, for example, whether errors in translation play a role in Alzheimer's disease and other degenerative brain diseases. Another possible direction - examining the question of whether these mistakes slow down or accelerate the development of cancer and what their role is in the aging process.

It will also be possible to investigate the possible role of translation errors in the evolution of species: the errors create a variety of different proteins that can help adapt to changing conditions. Prof. Pepper says: "The mistakes in the proteins create differences between genetically identical cells, and this diversity may benefit them during evolution."

DNA is replicated at a rate of about 1,000 "genetic letters" per second. The ribosome produces proteins at an average rate of about 10 amino acids per second.

for the scientific article

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One response

  1. This sounds like research worthy of a Nobel Prize. So important and revolutionary, with the potential for broad implications for evolution, genetics, medicine and even artificial intelligence. Why isn't the world shaking??

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