Researchers develop light-activated protein superglue for fast and precise control of cells and tissues

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AI-based artist rendering of light-activated control of cells. Credit: Protein Dynamics Group/University of Tampere

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AI-based artist rendering of light-activated control of cells. Credit: Protein Dynamics Group/University of Tampere

Researchers at the University of Tampere are involved in an international study to develop new tools for light-activated control of cells. These tools are particularly welcome for understanding the processes by which rapid early signaling leads to long-term changes in cell or tissue function. The modular Lego brick-like structure is a widely used tool in the study of various cellular functions.

Controlling biological activity with light has opened up new opportunities in various fields, especially in neuroscience. Light allows tightly controlled activation at a specific location and enables control at different scales, from individual cells to whole organisms. At the molecular level, optical control is often achieved through modified proteins that react to specific wavelengths of light.

However, with current instruments, effects are slow to appear, and continuous light activation is required for lasting effects. This both limits the applicability of these methods in the control of fast processes and leads to unwanted toxicity in the cells or organisms studied.

Together with research teams from the University of Cambridge and the University of Pittsburgh, researchers from the University of Tampere in Finland explored ways to overcome the limitations of current tools for light-regulation of cells. Building on their previous expertise in proteins that form irreversible bonds, the team aimed to achieve an ambitious goal: fast and cell-friendly regulation of irreversible protein binding.

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The resulting research paper, „Visible Light-Induced Specific Protein Reaction Illustrates Early Stages of Cell Adhesion,” Published In Journal of American Chemical Society.

As a starting point, the team used their previously developed „protein superglue,” a SpyTag003/SpyCatcher003 peptide/protein pair that exhibits very fast irreversible binding. Based on an engineered Streptococcus pyogenes protein, the SpyTag003/SpyCatcher003 peptide/protein pair allows the Lego brick-like modular assembly of complex protein systems.

To achieve their goal—optical control of the protein superglue—the team needed to reach beyond the 20 amino acids that make up human proteins. Using a protein synthesis machinery adapted from archaebacteria, the team incorporated a light-reactive unnatural amino acid into the SpyCatcher003 protein. The unnatural amino acid was strategically placed until activation by exposure to light to prevent peptide/protein conjugation.

„A short pulse of light is sufficient to induce the rapid and efficient formation of an irreversible peptide/protein complex in a test tube and in living cells,” says Professor Mark Howarth about the efficacy of photoactivated SpyCatcher003. „Importantly, activation occurred only with specific wavelengths of light, making it possible to combine protein control with live-cell fluorescence microscopy.”

Validating their approach to optical control of irreversible protein coupling, the team was interested in using the system to answer fundamental questions in cell biology. Human cells attach to surrounding tissues through cell adhesions; Large protein complexes containing hundreds of different proteins. Cell-matrix adhesions are highly dynamic, constantly responding to stimuli arising inside and outside the cell.

„Their dynamic structure and vast complexity make it difficult to study cell adhesions. The details of how cell-matrix adhesions form and how they respond to different stimuli are often unknown,” says Professor Vesa Hydtonen, who studies the regulation of cell adhesion. years.

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The team explored using newly developed tools to cleave talin, a central adhesion protein, into two parts and photo-activate the talin protein inside cells.

„We were very excited when we first realized how well the system works in controlling complex cellular processes such as adhesion and cell spreading. After activating the talin protein with short pulses of light, we observed an immediate cell response.” says postdoctoral research fellow Roel Rahikainen, lead author of the paper.

This tight control over adhesion formation allowed the team to investigate early events in the formation of cell adhesions. By tracking the timing of protein recruitment to the adhesion complex, the team was able to determine the timeline of events in adhesion complex formation. The findings demonstrated the ability of the light-activated protein Superglue to study complex cellular processes. The results also pave the way for a more detailed understanding of the complex structure and function of adhesion.

New tools for fast and irreversible protein conjugation are pushing the boundaries of what can be done with optical cell control. Rapid and irreversible protein aggregation is particularly valuable in processes where a short initial signal leads to long-term changes in cell or tissue function. Examples of such processes include regulation of gene expression during stem cell differentiation and activation of immune cells in viral infections. Importantly, the modular structure of the novel tools makes them widely applicable in controlling a variety of cellular processes.

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