Proteins at a distance

Villigen, 09/28/2021 – For the first time, researchers at the Paul Scherrer Institute PSI have linked two proteins with one another via a free-standing, rigid connection. The bridge link holds the two protein molecules at a defined distance and angle from one another – similar to the grip of a dumbbell between two weights. This type of link can, for example, help to develop so-called virus-like particles for vaccines. The researchers are publishing their results today in the journal Structure.

“Proteins have been optimized over millions of years in evolution,” says molecular biologist Roger Benoit from the PSI Laboratory for Biology in the Nanoscale. «Where proteins have to be rigid, they are in nature too. But imitating that in the laboratory is difficult. “

It is difficult for anyone who wants to link two proteins with one another via a protein bridge at a defined distance and angle. The link usually turns out to be too flexible, which means that the two proteins come too close. It’s like connecting two weights with a rope. As soon as you raise the rope until the weights can swing freely, the weights come closer to each other. When protein molecules come close, however, they can interact. The contacts between the proteins often restrict the natural freedom of movement in the structure – the molecules move differently than would be the case without contact with the other protein.

There would be many uses for connections with less flexibility, but it is difficult to design. “How the proteins fold and what their structure will look like in reality is often difficult to predict,” says Benoit. In other words: Several proteins can usually only be strung together at the desired distance and orientation with extremely complex optimization in the laboratory.

Roger Benoit and his team have now found a solution for this. They used a segment of a protein that is involved in, for example, wound healing in the human body. Part of this protein forms a helix, a kind of spiral. Their backbone is stabilized by interactions between their side chains. As a result, the helix remains intact on its own and is quite rigid – like a metal spiral made of hardened steel. In this way, Benoit successfully linked several proteins together in the desired manner.

Applied to the dumbbell analogy, this means that the researchers have now connected the proteins with a metal spiral instead of a rope, thereby keeping them at a constant distance. They also determined the orientation of the two proteins to one another.

Input for new vaccines

Such rigid connections have the potential for many practical applications. Among other things, it could help develop vaccines against viruses, including Sars-CoV-2.

Often times, vaccines are made by inactivating the pathogens. They can then no longer harm humans, but they stimulate the immune system to produce antibodies. Another possibility is offered by so-called virus-like particles, virus-like particles reproduced in the laboratory. Many characteristic surface proteins of a virus are attached to their surface so that the immune system perceives them and then also forms antibodies.

Virus-like particles offer the advantage that they do not contain any genetic material from the pathogen and thus there is no likelihood that they will multiply. They are therefore safer than weakened pathogens and are currently being researched for several viruses, such as hepatitis B and human papilloma viruses.

With the connector, the virus proteins can be attached more precisely to the surface of such virus-like particles. The rigidity of the helix offers advantages: “If the connection between the particle and the virus protein is too flexible, the proteins can possibly fold back again and are then no longer as present,” explains Benoit. The immune system recognizes them less well. If the proteins stick out more from the particles and all present themselves at a certain angle and distance, as is possible with the spacer, better and more effective vaccines can be developed with it.

Bone and silk

Benoit hopes that new biomaterials can also be created in this way. The helix could serve as a building block in combination with other proteins. In the future, researchers may be able to build 3-D protein scaffolds to replace a piece of bone, for example. “Or you can use it to tie proteins into long strings and create new silk-like textiles that are then even biodegradable.”

Researchers at PSI and at research institutes around the world who are working on the structure of proteins also benefit from the new method. Because protein molecules that are linked by the inflexible helix can be optimized so that they crystallize and retain their natural freedom of movement in the crystals. This makes it easier to examine their structure. With new methods of protein crystal structure analysis, for example with the free electron X-ray laser SwissFEL at PSI, even proteins can be observed in action, for example when membrane pumps transport substances out of the cell.

The results of the study will be published in the journal on September 28, 2021 Structure released.

Text: Paul Scherrer Institute / Brigitte Osterath

About the PSI
The Paul Scherrer Institute PSI develops, builds and operates large and complex research facilities and makes them available to the national and international research community. The company’s own research focuses on matter and material, energy and the environment, and people and health. The training of young people is a central concern of PSI. That is why around a quarter of our employees are postdocs, doctoral students or apprentices. PSI employs a total of 2100 people, making it the largest research institute in Switzerland. The annual budget is around CHF 400 million. PSI is part of the ETH Domain, which also includes ETH Zurich and ETH Lausanne as well as the research institutes Eawag, Empa and WSL.

Originalveröffentlichung

Chimeric single α-helical domains as rigid fusion protein connections for protein nanotechnology and structural biology
G. Collu, T. Bierig, A.-S. Krebs, S. Engilberge, N. Varma, R. Guixà-González, X. Deupi, V. Olieric, E. Poghosyan, RM Benoit
Structure,
28. September 2021 (online)
DOI: https://dx.doi.org/10.1016/j.str.2021.09.002


Address for queries

Dr. Roger Benoit
Laboratory for biology in the nanoscale
Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland
Phone: +41 56 310 47 03, E-Mail: [email protected] [Deutsch, Englisch, Französisch]


editor

Paul Scherrer Institute

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