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How does the body protect itself against harmful proteins?


Defective proteins are recognized and eliminated by the body
Our body has developed protective mechanisms against much impending damage, which are based on natural processes and which usually work relatively efficiently. These include, for example, the disposal of defective, in the worst case toxic proteins. Scientists at Charité - Universitätsmedizin Berlin have now deciphered how the faulty proteins are disposed of, which is of fundamental importance for the survival of a cell. This could also open up new therapeutic options, for example in the area of ​​neurodegenerative diseases, the researchers report.

The Charité scientists have found out how two special auxiliary proteins enable the eradication of defective proteins. They report in the journal "Nature Communications" how the defective messenger ribonucleic acid, which serves as "building instructions" for protein biosynthesis, is recognized and how its degradation is initiated. The two “rescue proteins” practically dispose of potentially defective compounds, which could also open up new options for the treatment of certain diseases, the scientists report.

Protein biosynthesis carefully analyzed
The research team led by Dr. According to Tarek Hilal from the Charité Institute of Medical Physics and Biophysics, genetic information stored in the genes is read out by the so-called ribosome during protein biosynthesis and converted into proteins. For this purpose, the information stored in the chromosomes is first translated into a mobile form, the so-called messenger ribonucleic acid (mRNA), which can then be read to the ribosome and then used as an exact blueprint for the production of the proteins. A faulty mRNA results in the production of defective, possibly harmful proteins, which is why the researchers have to recognize and break it down efficiently.

Faulty mRNA blocks the ribosomes
In the current study, the researchers used mRNAs without a stop signal to investigate which mechanisms are used here in the body to eliminate the defective messenger ribonucleic acid. If the “non-stop mRNAs” are read by the ribosome, the entire process stagnates and there is no orderly termination of the protein biosythesis, the researchers explain the effect of the faulty mRNA. As a result, the ribosome cannot take any further action and remains blocked.

Auxiliary proteins resolve blockages
Using so-called cryo-electron microscopy, the researchers analyzed the structure of the blocked compounds from ribosomes and mRNA and were able to demonstrate that special auxiliary proteins (Dom34 and Hbs1) recognize ribosomes locked in this way and initiate the dissolution of the blocked complexes and the breakdown of the mRNA, the Charité scientists report. The two auxiliary proteins would only tap conserved areas of the ribosome that are typically occupied by mRNA, the experts further explain. This competitive binding mode ensures that only ribosomes are attacked on defective mRNAs.

Hope for new therapeutic options
Director of Studies Dr. Tarek Hilal emphasizes that "research into the effects of defective mRNAs and the consequences of insufficient degradation is becoming increasingly important". In particular in the case of neurodegenerative diseases such as, for example, amyotrophic lateral sclerosis (ALS), faulty mRNAs can be identified and “a molecular understanding of the cellular control mechanisms can therefore be helpful in order to find starting points for therapeutic purposes,” the expert hopes. (fp)

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