In a landmark scientific achievement published in Nature as a set of two papers (article 1 and 2), researchers designed and validated a functional protein switch entirely from scratch. While expression of proteins de novo has previously been accomplished, generating a dynamic protein that is functionally able to transition through different conformational states is no simple feat of engineering.

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. 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 pRoteins’ (LOCKR).

The researchers went on to validate the specific and singular functionality of the LOCKR system as a switch in a variety of important cell signaling pathways such as apoptosis, degradation, cellular trafficking in vitro and in vivo. Additionally, they demonstrated how 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.

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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