SpySwitches: switchable SpyCatcher interactions yielding a modular toolbox for biochemistry and cell biology

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Most of the processes that keep us alive are carried out by proteins. The majority of proteins do not act on their own but work in partnership with other proteins. Therefore, understanding how and where proteins interact is an important challenge. Some of these interactions only last for a fraction of a second, while others can last for days. We previously generated a "bacterial superglue" called SpyCatcher, which forms one of the strongest protein interactions ever found. SpyCatcher has found many uses, such as for accelerating creation of new vaccines or for building diagnostics to sequence DNA. In this proposal we will use evolution and design to engineer the next generation of SpyCatcher technology. We will generate new versions of SpyCatcher that span the full range of protein interactions, from one that breaks in seconds, another that breaks in minutes, all the way to the original that never breaks. We will also make versions of SpyCatcher that respond to acidic conditions or to light, so that researchers can turn the interaction on as desired. This unprecedented control over protein interactions should have many applications for basic research and biotechnology. In particular we will study how interactions in a cell change according to the mechanical stresses, as occurs when cells explore their surroundings or when a muscle contracts.