Exploiting protein domain modularity to enable synthetic control of engineered cells

The ability to precisely control cellular function in response to external stimuli can enhance the function and safety of cell therapies. In this review, we will detail how the modularity of protein domains has been exploited for cellular control applications, specifically through design of multifunctional synthetic constructs and controllable split moieties. These advances, which build on techniques developed by biologists, protein chemists and drug developers, harness natural evolutionary tendencies of protein domain fusion and fission. In this light, we will highlight recent advances towards the development of novel immunoreceptors, base editors, and cytokines that have achieved intriguing therapeutic potential by taking advantage of well-known protein evolutionary phenomena and have helped cells learn new tricks via synthetic biology. In general, protein modularity, i.e., the relatively facile separation or (re)assembly of functional single protein domains or subdomains, is becoming an enabling phenomenon for cellular engineering by allowing enhanced control of phenotypic responses.