When cells interact with their environment via receptors at their surface, the receptors can bind to hormones, neurotransmitters, drugs, and toxins which can trigger signaling inside the cell. Now, proteins have been engineered to form honeycomb structures that can block these interactions with living cells without being absorbed by them. These designer protein patches can influence cell signaling by binding and sequestering cell surface receptors and could have far-reaching implications for stem cell research and enable the development of new materials designed to modulate the behavior of living systems.

The research is published in Nature in the paper titled, “Design of biologically active binary protein 2D materials.

The research was led by the labs of David Baker, PhD, head of the Institute for Protein Design and professor of biochemistry at the University of Washington (UW) School of Medicine and Emmanuel Derivery, PhD, group leader at the Medical Research Council Laboratory of Molecular Biology at Cambridge University.

For the cell, it is important that the interactions that influence signaling are transient, so that the cell can remain responsive to future signals. To achieve this, cells will commonly terminate signaling by absorbing both an activated receptor and the molecule that stimulated it, thereby targeting both for destruction inside the cell.

“This tendency of cells to internalize receptors likely lowers the efficiency of immunotherapies,” said Derivery. “Indeed, when antibody drugs bind their target receptors and then become internalized and degraded, more antibody must always be injected.”

To create a way around this, Ariel Ben-Sasson, PhD, a postdoctoral scholar in the Baker lab, designed new proteins that assemble into large, flat patches. This molecular scaffolding was then further engineered to contain signaling molecules.

Graduate student Joseph Watson of the Derivery lab showed that such protein materials could latch onto cells, activate surface receptors, and resist being absorbed by the cell for hours or even days.

The authors wrote that “materials composed of two components have considerable potential advantages for modulating assembly dynamics and incorporating more complex functionality.”

Because the material is designed from the ground up, the authors added, the components “can be readily functionalized and their symmetry reconfigured, enabling formation of ligand arrays with distinguishable surfaces, which we demonstrate can drive extensive receptor clustering, downstream protein recruitment, and signaling.”

“This work paves the way towards a synthetic cell biology, where a new generation of multi-protein materials can be designed to control the complex behavior of cells,” said Baker.

By swapping out which cell surface receptors were targeted by the patch, the researchers showed that different cell types could be activated.

“We now have a tool that can interact with any type of cell in a very specific way,” said Ben-Sasson. “This is what is exciting about protein engineering: it opens fields that people may not expect.”

The authors explained that, in contrast to previously characterized cell surface receptor binding assemblies such as antibodies and nanocages, which are rapidly endocytosed, “large arrays assembled at the cell surface suppress endocytosis in a tunable manner, with potential therapeutic relevance for extending receptor engagement and immune evasion.”

According to co-author Hannele Ruohola-Baker, professor of biochemistry at the UW School of Medicine and associate director of the UW Medicine Institute for Stem Cell and Regenerative Medicine, versions of these new materials could eventually help physicians alleviate the dangers of sepsis by controlling the inflammatory response to infection.

They might even enable entirely new ways to treat COVID-19, heart disease, and diabetes, and perhaps mitigate the downstream effects of strokes, including Alzheimer’s disease.

“This breakthrough helps pave the way for the use of synthetic cell biology in regenerative medicine,” said Ruohola-Baker.

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