Moonlighting is mainstream: Paradigm adjustment required

Moonlighting – the performance of more than one function by a single protein – is becoming recognized as a common phenomenon with important implications for systems biology and human health. The different functions of a moonlighting protein may use different regions of the protein structure, or alternative structures that occur due to post‐translational modifications and/or differences in binding partners. Often the different functions of moonlighting proteins are used at different times or in different places. The existence of moonlighting functions complicates efforts to understand metabolic and regulatory networks, as well as physiological and pathological processes in organisms. Because moonlighting functions can play important roles in disease processes, an improved understanding of moonlighting proteins will provide new opportunities for pharmacological manipulations that specifically target a function involved in pathology while sparing physiologically important functions. Moonlighting proteins have acquired one or more additional functions ‐ with respect to their canonical function ‐ during evolution. This phenomenon seems to be more widespread than previously thought. This review presents the structural basis of moonlighting and discusses numerous examples.