"Protein Clamp" protects rabies virus

High-resolution structural images show how viral shields work

Protective logo of the rabies virus © EMBL
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There is no cure for rabies today. But how does the rabies virus manage to withstand the human immune system so effectively? Scientists have now obtained a detailed structural picture of a protein that allows the virus to survive undisturbed in the cells and multiply. The study, which is now published in Science, offers new approaches to therapy - including other diseases caused by RNA viruses, such as Ebola and measles.

Once the rabies virus has entered the nervous system and brain from the point of infection via the blood, every treatment is almost ineffective. There is a vaccine against rabies, but no remedy that works even after the early phase of the infection. The trigger for the deadly disease is, like Ebola and measles, an RNA virus. The viruses of this class have not preserved their genetic information like most other living things in the double helix of the DNA, but in a single-stranded RNA. It is channeled into the cell nucleus of the host cells after infection, causing the cell's own machinery to replicate.

Protein as a protective shield

But for this to work, a protein, the so-called nucleoprotein, plays a crucial role. It ensures that viral RNA is not destroyed by the host's immune response as it passes through the cell. "The nucleoprotein is existential for the rabies virus, " explains Rob Ruigrok, director of the Institute of Molecular and Structural Virology (IVMS). "It is one of the few proteins that the virus brings to the host cell and that is wrapped around its RNA like a protective shield. Without this shield, the RNA would be degraded by the attacking enzymes of the human immune system. "

Together with colleagues from the field office of the European Molecular Biology Laboratory (EMBL) in Grenoble, Ruigrok investigated how this shield works. For this purpose, the researchers first created crystals of the nucleoprotein bound to the RNA. Using the strong X-ray source at the European Synchrotron Beam Facility (ESRF), they were able to obtain a high-resolution picture of the structure of this protein.

Clamp with swiveling "pines"

"The nucleoprotein acts like a clamp, " explains Winfried Weissenhorn from EMBL. "It consists of two domains that cover the RNA strand like two jaws. Many of these nucleoproteins bind side by side across the length of the RNA strand, making it inaccessible to the degrading enzymes as well as the machinery that replicates the virus. Therefore, the shield must be flexible and able to distinguish between the different types of enzymes. "Display

The detailed structural picture suggests that, in response to a specific signal, a protein portion acts as a hinge and swings the "maxilla" out of the way, when a replication enzyme is targeted. "This dynamic process makes the nucleoprotein an excellent target molecule for us, " says Ruigrok. Small compounds that bind to the protein in such a way that they block its flexibility and keep it in a permanently closed state could prevent the replication of the virus and thus stop its spread.

The rabies virus shares this protection strategy with other viruses of its class: Also found in Ebola, measles and the Bornavirus sore similar proteins. This means that our results not only impact on the development of new rabies, but also provide new therapeutic approaches to a whole range of diseases, some of which are even more threatening than rabies We, explains Weissenhorn. "In another aspect, the nucleoprotein system also provides scope for evolutionary biology speculation on common ancestors and primal RNA RNA infection units."

(EMBL, 19.06.2006 - NPO)