Two proteins were stably joined for the first time

Two proteins were stably joined for the first time

At the Paul Scherrer Institute a rigid and independent spiral protein bond was constructed, capable of having predefined distances and angles

Rendering of the protein bridge principle developed at PSI in Switzerland: Two proteins (A and B) are connected to each other at a fixed distance and angle by means of a rigid protein spiral, so that they cannot approach each other and cannot interact (Graphic: Mahir Dzambegovic/Paul Scherrer Institute)
Rendering of the protein bridge principle developed at PSI in Switzerland: Two proteins (A and B) are connected to each other at a fixed distance and angle by means of a rigid protein spiral so that they cannot approach each other and they cannot interact
(Graphic: Mahir Dzambegovic/Paul Scherrer Institute)

The researchers ofPaul Scherrer Institute, research institution belonging to the sector of Federal Polytechnics of the Helvetic Confederation, were the first to have joined two proteins by means of a rigid and independent connection.
The structural element holds the two protein molecules together at a predefined distance and angle, just like the handle of a balance wheel connects two weights.
This type of connection could help, for example, to develop so-called “virus-like particles” to obtain vaccines, especially since i Swiss researchers have already reported their findings in the trade journal "Structures".
The article, published online on 28 September 2021 at the URL address https://dx.doi.org/10.1016/j.str.2021.09.002 and signed by Gabriella Collu, Tobias Bierig, Anna-Sophia Krebs, Sylvain Engilberge, Niveditha Varma, Ramon Guixà-González, Timothy Sharpe, Xavier Deupi, Vincent Olieric, Emiliya Poghosyan and Roger M. Benoit, is titled in English “Chimeric single α-helical domains as rigid fusion protein connections for protein nanotechnology and structural biology”.

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The headquarters of the Paul Scherrer Institute in Würenlingen in the canton of Aargau
The headquarters of the Paul Scherrer Institute in Würenlingen in the canton of Aargau

“So far difficult to imitate natural protein stiffness in vitro”

“Proteins have been optimized by the process of evolution over millions of years”, says the molecular biologist Roger benoit of the Laboratory for Nanoscale Biology of the PSI.
“In nature, where proteins need to be stiff, they are. But it is difficult to imitate them in vitro”.
If you want combine two proteins and keep them at a distance and angle defined by a protein bridge, the operation is generally very complex. L'connecting element it usually turns out to be too flexibleand, allowing the two proteins to get too close to each other.
It's like they bond two weights with a rope. As soon as you lift the cord so that the weights can swing freely, they fatally “touch”. When protein molecules get close to each other, however, they can interact.
I contacts between proteins often limit the natural freedom of movement of the overall structure: the molecules move differently than they would if there was no contact with the other protein.
There could be many applications for bonds with less flexibility, but designing them is difficult.
“Often, it is difficult to predict how proteins fold and what their structure looks like in reality”, says Roger Benoit.
That is, line up different proteins with the desired spacing and orientation usually requires aextremely complex optimization in the laboratory.
Roger Benoit and his team have now found a solution. They used a segment of a protein which plays a role, for example, in the wound healing in the human body. A part of this protein forms a helix, a spiral element.
La his backbone is stabilized by interactions between side chains. Thus, the prop remains intact on its own and is stiff enough, almost like one metal spiral in Tempered steel. With this, the scientists of theresearch institute in the Aargau He managed to connect different proteins to each other in the way you want.
In terms of analogy with a balance wheel, which means that the researchers have now linked the proteins together using a metal spiral instead of a rope, thus keeping distance constant between them. In this way, they also have orientation set of the two proteins relative to each other.

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Hemoglobin, antibody and collagen: the three-dimensional shape of a protein is uniquely suited to its function, so that twenty different blocks of amino acids can be arranged in different ways to form an almost infinite assortment of protein shapes
Hemoglobin, antibody and collagen: the three-dimensional shape of a protein is uniquely suited to its function, so that twenty different blocks of amino acids can be arranged in different ways to form an almost infinite assortment of protein shapes

Will the "protein link" be the input towards new vaccines?

These hard connections have considerable potential for many practical applications. Among other things, they could prove useful in the vaccine development against viruses, including the COVID-2.
Vaccines are often produced by making vaccines inactive pathogens. They can no longer harm humans, but stimulate the immune system to produce antibodies. The virus-like particles are prepared in the laboratory an alternative option.
Many surface proteins characteristics of a virus are attached to the tops of these virus-like particles, so that the immune system detects them and generate antibodies.
An advantage offered by virus-like particles is that, since they they do not contain genetic material ofpathogen, there is no chance of them multiplying.
For this reason, they are safer than weakened pathogens, and are currently being studied for the protection against different viruses, Such as'hepatitis B and papilloma virus of mankind.
With the company rigid connector constructed between Villigen and Würenlingen, le virus proteins could be attached to surfacesand of such virus-like particles more precisely.
La limited propeller flexibility offers advantages: “If the connection between the particle and the virus protein were too flexible, the proteins could fold up again, and then they would no longer be accessible”, explains Roger benoit.
Il immune system he doesn't recognize them as well. If the proteins they stand out more from the particles and they all show up at a predetermined angle and distance, as is possible with the Swiss made spacer, they could develop better vaccines and more effective.
The Swiss researcher hopes that new biomaterials can be created this way. The prop could serve as a building block in combination with other proteins.

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The SwissFEL (Switzerland's X-ray Free-Electron Laser) infrastructure building in Switzerland
The SwissFEL (Switzerland's X-ray Free-Electron Laser) infrastructure building in Switzerland

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In the future, researchers may be able to build protein scaffolding in 3D, for example, for replace a piece of bone.
“Or it could be used to combine proteins into long strings and create new silk-like fabrics, which then could also be biodegradable.”
Also PSI researchers and research institutions around the world working on understanding protein structure could and, perhaps, should benefit from the new method.
This because protein molecules connected to each other via the rigid helix could be optimized so as to obtain forms of crystallization and yet keep their natural freedom of movement in the crystals. This would make it easier to examine their structure.
With the new methods of structural analysis of the protein crystals, for example, using the free electron lasers of the SwissFEL (Switzerland's X-ray Free-Electron Laser) available at the laboratories of thePaul Scherrer Institute, protein can also be observe in action, for example when the diaphragm pumps carry substances out of a cell.

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Roger Benoit at the light transmission instrument of the Swiss Light Source SLS of PSI, where he determined the structure necessary for the binding of two proteins (Photo: Mahir Dzambegovic/Paul Scherrer Institute)
Roger Benoit at the light transmission instrument of the Swiss Light Source SLS of the PSI, where he determined the structure necessary for the binding between two proteins
(Photo: Mahir Dzambegovic/Paul Scherrer Institute)