Protein scissors activate the protective function

Nature (2022). DOI: 10.1038/s41586-022-05571-7″ width=”800″ height=”530″/>

Uncropped and unedited version of all gels used in this study. The red frame indicates the fraction of the gel that is shown in the images shown. credit: Nature (2022). DOI: 10.1038/s41586-022-05571-7

For several years now, the CRISPR/Cas9 gene scissors have been making waves in science and medicine. This new molecular biology tool has its origins in the ancient bacterial immune system. It protects bacteria from attack by so-called phages (viruses that infect bacteria).

Researchers from the Institute of Structural Biology of the University Hospital Bonn (UKB) and the Faculty of Medicine of the University of Bonn, in collaboration with the partner University of St. Andrews in Scotland and the European Laboratory of Molecular Biology in Hamburg, have discovered a new function of gene scissors. The study was published in Nature.

Bacteria and phages have been engaged in a life-and-death struggle on Earth since time immemorial. When an attacking phage injects its genetic material into a bacterium, it is forced to produce new phages, which in turn infect more bacteria. In response, some bacteria have developed the CRISPR system. With this bacterial immune system phage genetic material is recognized and destroyed.

At the same time, the obtained fragments are integrated into the genome of the bacterium. This creates a kind of library that the CRISPR immune system can access again and again and thus weaponize for future attacks. In addition, so-called type III variants of the scissor gene were found to produce small signaling molecules. With the help of these small molecules, the bacteria put together a complex emergency plan. This ensures that the virus can be fought optimally and with a broad front.

Researchers from the Institute of Structural Biology at the University Hospital Bonn (UKB) and the Faculty of Medicine at the University of Bonn have now investigated how this works in collaboration with scientists from the partner University of St Andrews in Scotland and the European Laboratory for Molecular Biology in Hamburg. The research team discovered that the small signaling molecules bind to, among other things, a protein called CalpL, which thus becomes an active “protease”.

These are enzymes that break down proteins and thus function as protein scissors. “Proteases are also used in humans immune system transmit information at a high speed,” says Nils Schneberger, a doctoral student at the Institute of Structural Biology at the UKB and one of the two first authors of the study.

Finally, the researchers also found a target for their newly discovered scissor protein. It cuts a small protein molecule called CalpT, which acts as a latch for CalpS, a third protein molecule: “CalpS is a very well-protected protein that is released by the whole mechanism. It will translate the transcription mechanism into specific genes, switching the bacterium’s metabolism to a defensive one. We are very interested [to know] what are these genes,” explains Christophe Rouillon, who is a visiting scientist at the Institute of Structural Biology and first author of the study.

With the discovery of this complex signaling cascade, researchers have discovered an entirely new aspect of CRISPR systems.

The great thing about CRISPR systems is also that they can be very easily reprogrammed for biotechnological and medical purposes. With CRISPR, DNA can be specifically modified, that is, genes or entire blocks genes can be pasted or cut. Some diseases such as spinal muscular atrophy (SMA), which leads to nerve paralysis, can already be treated with gene scissors.

“With this activated CRISPR protein scissors, now there’s a whole new tool in the molecular biology toolbox,” says Dr. Gregor Hageluken, group leader at UKB’s Institute of Structural Biology and member of the university’s transdisciplinary Life and Health research area. “And maybe it will allow CRISPR to be used in the future in even more diverse ways,” he adds.

Additional information:
Christophe Rouillon et al., Antiviral Signaling by Cyclic Nucleotide-Activated CRISPR Protease, Nature (2022). DOI: 10.1038/s41586-022-05571-7

Courtesy of University Hospital Bonn (UKB)

Citation: New function of CRISPR gene scissors discovered: Protein scissors activate defense function (November 25, 2022) Retrieved November 25, 2022, from .html

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