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De novo-designed Bioactive Protein Switch Controls Biological Processes in Living Cells

protein engineering, synthetic biology, LOCKR, combinatorial DNA library, metabolic engineeringIn a landmark scientific achievement published recently in two companion papers in Nature (article 1 and 2), a team of bioengineers designed and validated a functional protein switch entirely from scratch and have used it to control biological processes in human cells. While expression of proteins de novo has previously been accomplished, generating a dynamic protein whose function can be controlled by induced conformational changes within living cells is no simple feat of engineering. These de novo-designed proteins hold great promise as building blocks for synthetic circuits and being able to control protein function in living cells opens up the possibilities for addressing challenges researchers face currently in synthetic biology.

This artificial, synthetic protein, known as a ‘switch’, resembles a cage and contains a helical arm which acts as a ‘latch’. The binding of a specific ‘key’, typically a small peptide, induces conformational changes within the switch and leads to the opening of the latch, effectively turning the switch ‘on’. Only on latch opening would a user-defined, bioactive peptide sequence located within the switch be revealed. The newly exposed peptide can then bind a target molecule to activate downstream effector functions. Researchers termed this tunable switch-key system the ‘Latching Orthogonal Cage-Key pRotein’ (LOCKR).

Interestingly, this ‘latch’ can be engineered to control any cellular process such as direct molecular traffic inside of cells, degrade specific proteins, and initiate the cell’s self-destruct process. In order to validate the specific and singular functionality of the LOCKR system as a switch, the scientists built LOCKR with pathway specific peptides whose function was only turned on when specific ‘keys’ were expressed. The researchers showed that they were able to control a variety of important cell signaling pathways such as apoptosis, degradation, cellular trafficking in vitro and in vivo. Additionally, researchers linked the proteins together into synthetic circuits, which expressed both the LOCKR protein and small peptide necessary to unlock the function of LOCKR, in order to control the inner workings of yeast. They demonstrated the LOCKR system could be engineered to implement tunable feedback control within endogenous and synthetic signaling circuits in yeast as well as in mammalian cells.

This research highlights the great potential of using these ‘designer’ proteins as tools within living cells in a multitude of ways, such as improving therapies and correcting aberrations in cellular signaling circuitry. LOCKR provides an unprecedented control over the way a protein interacts with components of the cell. Using this switch-like protein, synthetic biologists can now build biological circuits to control the function of human cells, opening the doors for novel cellular therapies.

Langan RA, Boyken SE, Ng AH, et al. De novo design of bioactive protein switches. Nature. (2019). https://doi.org/10.1038/s41586-019-1432-8

Ng AH, Nguyen TH, Gómez-Schiavon M, et al. Modular and tunable biological feedback control using a de novo protein switch. Nature. (2019). 10.1038/s41586-019-1425-7

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