Smart proteins, the dawn of new intra-cell therapeutics

Saw an article the other day about Smart Cells (Incredible artificial proteins opens up potential for smart cells). There’s another paper that goes into a bit more depth than the original article (‘Limitless potential’ of artificial proteins ushers in new era of ‘smart’ cell therapies).

The two freely available articles talk about two papers in Nature (De novo design of bioactive protein switches & Modular and tunable biological feedback using a de novo protein switch, behind a paywall) that explain the technology in more detail.

Smart proteins act as switches

What the researchers have created is an artificial protein that builds a cage around some bioactive (protein based) mechanism that can be unlocked by another protein while residing in a cell. This new protein is called LOCKR (Latcheable Orthogonal Cage-Key pRotein). LOCKR proteins act as switch activated therapeutics within a cell.

In the picture above the blue coils are the cage proteins and the yellow coil is the bioactive device (protein). Bioactive devices can be designed that degrade other proteins, can modify biological processes within the cell, initiate the cells self-destruct mechanism, etc, just about anything a protein can do within a cell.

In the second Nature paper, they discuss one example of a LOCKR protein, called degron-LOCKR which once inside a cell is used to degrade (destroy) a specific protein. The degron-LOCKR protein only activates when the other protein is active (found) within the cell and it operates only as long as that protein is in sufficient concentration.

The nice thing about the degron-LOCKR protein is that is completely self-regulating. It only operates when the protein to be degraded exists in the cell. That protein acts as the switch in this LOCKR. Until then it remains benign, waiting for a time when the targeted protein starts to be present in the cell.

How LOCKR works

In the picture above the cage is in shown by the grey structure, the bio-active therapy is shown by the yellow structure, and the protein key is shown by the black structure. When the key is introduced into the LOCKR protein, the yellow structure is unfolded (enabled) and can then impact whatever intra-cellular process/protein, it’s been designed to impact.

One key attribute to LOCKR is that the bioactive device within the cage, can be just about anything that works inside the cell. It could be used to create more proteins, less proteins, disable proteins, and perhaps enhance the activity of other proteins.

And, both the LOCKR and the bioactive device can be designed from scratch and fabricated outside or inside the cell. Of course the protein key is the other aspect of the LOCKR mechanism that is fully determined by the designer of the LOCKR protein.

Sort of reminds me of the transistor. Both are essentially switches. For transistors, as long as voltage is applied, it will allow current to flow across the switch. LOCKR does something very similar, but uses a key protein and a bioactive protein that only allows the bioactive protein to activate when the key protein is present.

We’ve talked extensively in the past about using DNA/cells as rudimentary computers and storage, but this takes that technology to a whole other level, (please see our DNA computing series here & here as well as our posts on DNA as storage here & here ). And all that work was done without LOCKR. With LOCKR much of these systems would be even easier to construct and design.

The articles go on to say that LOCKR unleashes the dawn of a new age of intra-cell therapeutics with fine grained control over when and where a particular bio-active therapy is activated within the cell

Some questions

Some of these may be answered in the Nature papers (behind paywall), so sorry in advance, if you have access to those.

How the LOCKR protein(s) are introduced into cells, was not discussed in the freely available articles. We presume that DNA designed to create the LOCKR protein could be injected into cells via a virus, added to the cells DNA via CRISPR, or the LOCKR protein could just be injected into the cell.

Moreover, how LOCKR proteins are scaled up within the cell to be more or less active and scaled up throughout an organ to “fix” multiple cells is yet another question.

Adding artificial DNA or LOCKR proteins to cells may be easy in the lab, but putting such therapy into medical practice will take much time and effort. And any side effects of introducing artificial DNA or LOCKR proteins (not found in nature) to cells will need to be investigated. And finally how such protein technology impacts germ lines would need to be fully understood.

But the fact that the therapeutic process is only active when unlocked by another key protein makes for an intriguing possibility. You would need both the LOCKR protein and the key (unlock-er) protein to be present in a cell for the therapy to be active.

But they present one example, the degron-LOCKR, where the key seems to be a naturally active protein in a cell that needs to be degraded, not a different, artificial protein introduced into the cell. So the key doesn’t have to be an artificial protein and probably would not be for most LOCKR designed proteins.


Not a bad start for a new therapy. It has much potential, especially if it can be scaled easily and targeted specifically. Both of which seem doable (given our limited understanding of biological processes).


Picture Credit(s): From De novo design of bioactive protein switches article

From Limitless potential… article