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New proteins enable scientists to control cell activities


New proteins allow scientists to control cell activity

FIG. 1: Overview of structure-based design strategies used to create new reactive switches with small molecules. These design strategies include: (I) binding site transplantation to create new CDHs (a) that can be used to control cellular activities; (II) Interface mutations for affinity tuning (b) to alter drug concentrations that interfere with the assembly of the complexes; (III) Multi-state design to create drug-sensitive receptors embedded in multi-domain architecture that dim on drug exposure (c). This protein switch toolbar increases the chemical space (d) and can be used to create cells that detect different chemical signals and output a variety of signals (e). Credit: DOI: 10.1038 / s41467-021-25735-9

Sailan Shui, a PhD Assistant at EPFL’s Laboratory of Protein Design and Immunoengineering, enjoys playing with proteins, activating and deactivating them as she pleases, as well as light switches that can be turned on and off. Instead of using electronics, however, their method relies on proteins to activate the process. Shui’s research has just been published in Nature communication.

To develop their method, Shui and her colleagues began by computationally modeling proteins that do not exist naturally. They then collect proteins in OFF and ON switches. “The first step was to combine the two synthetic proteins together and ensure that they can work in tandem. One protein acts as a cement, glues the whole structure together, and the other is a medicine receptor. We also had to find two proteins that ‘ t form strong, stable tires so that they stay attached, “says Shui.

A molecule rotates the switch

Once the protein pairs were formed, the next step was to find a third type of molecule that could alternatively bind and activate the existing structure, or break apart and deactivate. Shui designed its systems to respond to a clinically approved drug Venetoclax. This drug is usually administered to treat cancer, but the scientist discovered a new use for it. “I basically transformed Venetoclax into an on / off switch for the proteins,” says Shui.

When the medicine comes in contact with the proteins, it has the ability to activate or separate them and therefore deactivate them. “In our method, it is the Venetoclax molecules that serve as the light switch. They are the ones that activate or deactivate the proteins,” she says. This means she can control when the proteins are activated, and for how long.

Monitor cell activity

The hope is that these protein switches can one day be used as intermediates with cells within the human body. “For example, we could place the protein switches in specific cells so that they can be activated as we wish,” says Shui. “That way, when we’re ready, we can apply the stimulus and observe the cellular response.” Bruno Correia, head of the EPFL lab where Shui conducts her research, adds: “This type of protein circuit, where the same compound serves two diametrically opposed functions, can be a promising method for controlling security and efficiency of custom cells. ”

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More information:
Sailan Shui et al, A Rational Blueprint for the Design of Chemically Controlled Protein Switches, Nature communication (2021). DOI: 10.1038 / s41467-021-25735-9

Delivered by Ecole Polytechnique Federale de Lausanne

Citation: New proteins allow scientists to monitor cell activity (2021, October 14) Retrieved October 14, 2021 from

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