Researchers from University of California, San Francisco and the University of Washington have developed a new artificial protein switch, dubbed LOCKR. Their work demonstrates that the new switch can be used to control many intracellular processes, including mediating molecular traffic inside a cell, degrading specific proteins, and causing a cell to self-destruct. This exciting development can be used in next generation cell therapies, such as CAR-T cell therapy for cancer.
Medicine often faces a Goldilocks problem: too much of a drug can be lethal while too little has no therapeutic effect. In the case of CAR-T cell therapy, some patients suffer organ failure due to overactivity of the transfused cells. Others see limited effectiveness due to inadequate activity. To address these limitations, the UCSF researchers developed a new artificial protein switch, which can serve as a switchboard to control various cellular activities.
LOCKR is a protein that takes the form of a barrel. When opened, it reveals a molecular arm that can control many cellular processes. The barrel can only be opened with a unique key, so the researchers can control the opening and downstream events.
The team used LOCKR in many scenarios, including directing molecular traffic inside a cell, degrading specific proteins, and initiating the cell’s self-destruct process. They also developed a version of the tool called degronLOCKR which can be used to degrade a specific protein of interest. They implemented degronLOCKR to dynamically regulate cellular activity in response to intracellular and extracellular cues. This exciting development may one day be used in living cell therapies, to make them smarter, more controlled, and more personalized.
“In the same way that integrated circuits enabled the explosion of the computer chip industry, these versatile and dynamic biological switches could soon unlock precise control over the behavior of living cells and, ultimately, our health,” said El-Samad, who is also a Chan Zuckerberg Biohub Investigator.
Image caption: LOCKR in its closed (background) and open (foreground) states. A ‘key’ (black) unlocks a ‘cage’ (grey), revealing a bioactive peptide (yellow) which can interact with other molecules in the cell. Credit: Ian Haydon / Institute for Protein Design at UW.