Engineering protein modules for diagnostic applications

•Domain swapping is a powerful method to generate protein sensing modules.•Individual protein domains can be combined into a cooperative input–output mechanism.•Trade-off between domain modularity and function integration on sensing

Proteins that communicate a biological event (either ligand binding, enzymatic modification, or protease cleavage) into a measurable output are highly desirable for diagnostic applications. Since many biological functions are naturally regulated using a similar principle, synthetic protein sensing modules can be created by joining these individual protein domains into a cooperative input–output mechanism. In this review, creative efforts toward formulating these synthetic sensing modules and the future opportunities and challenges will be discussed.