Virology: Sabotage in a different frame

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Virology: Sabotage in a different frame
Virology: Sabotage in a different frame

Sabotage in another frame

Some people tie knots in handkerchiefs to remember important things. Viruses also make knots, but in their genetic material. This is absolutely vital for them – and possibly for us too. Maybe that's an Achilles' heel of HIV and the Sars pathogen? Viruses are completely helpless on their own. Everything the Sars pathogen brings to our cells is its blueprint. Without our protein machinery, he'd be like an architect without carpenters. As a virus, it is also easier to travel with light luggage. You can still have all the essentials with you even with little baggage.

The blueprint of the Sars pathogen is its messenger RNA, the mRNA. It consists of a chain of nucleotides lined up next to each other, in which the amino acid code for the construction of proteins lies hidden. Three consecutive nucleotides code for a protein building block - i.e. nucleotides 1, 2 and 3 for the first amino acid x. This is the same for all organisms from plants to humans. However, viruses often use tricks to pack more efficiently: they nest the three-frame code of the mRNA. Some nucleotides therefore belong to two frames that code for different proteins: Two blueprints are thus found in one mRNA. In such viruses, nucleotides 2, 3 and 4 could also encode the first building block of a completely different protein.

If the Sars pathogen smuggles its nested messenger RNA into our cells, the body's own protein factories, the ribosomes, convert the amino acid code of the mRNA directly into proteins. The transfer RNA, the tRNA, is required for this: It binds to the complementary nucleotide sequence of the mRNA in the ribosome via an anticodon and is loaded with the amino acid determined by the codon. Then the correctly lined up amino acids of the tRNA only have to be linked.

But the more efficient virus mRNA contains two building instructions, which forces the ribosome to make a decision: which one will be implemented? Of course both. To do this, however, the virus has to use a little trick: it forces a shift in the reading frame, i.e. the three-frame code of the mRNA, which encodes the amino acids. In doing so, the ribosome somehow slides back one nucleotide position into a different reading frame, i.e. a different blueprint.

For the first time, Ian Brierley and his colleagues from the University of Cambridge have succeeded in practically confirming a theory that explains how the reading frame shifts. The researchers isolated mRNA from a coronavirus and added it to ribosomes from rabbit red blood cells. They identified an intermediate product from this complex, froze it, took a look at the frozen sample under the microscope – and were thrilled.

The virus had thrown a spanner in the works for the ribosome with its tools, the researchers realized under the microscope. It looked like a defective miniature clockwork: parts of the ribosome were blocked, the tRNA was twisted and had detached itself from the complex like a broken spring.

The virus itself brings the tools for the targeted work of destruction and the nucleotide-precise reading frame shift - a "pseudoknot" and a "nucleotide slip sequence". This is an mRNA nucleotide sequence over which the ribosome slides into the other frame and a sequence that forms a knot-like secondary structure in the mRNA, the pseudoknot.

The pseudoknot interacts with the ribosome, blocking protein synthesis for a short time, ensuring that the ribosome is placed in proximity to the slip frequency. The resulting tension causes the tRNA to twist, detaching itself from the machinery and allowing the ribosome to slip into a different reading frame via the slip frequency-targeted, of course.

Not only the Sars pathogen belonging to the corona virus, but also the HI virus knows how to sabotage the genetic code of the host in this way. If researchers prevent the reading frame of the HI virus from shifting, it is actually possible to prevent the pathogen from multiplying.

It may be some time before we use medicines to specifically sabotage the saboteur. Still, thanks to Ian Brierley and his staff, we can now keep a very close eye on him.

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