Hidden protein functions and what they may teach us

Bottom-up synthetic biology is a new research field with the goal of constructing living systems from a minimal number of functional components. The key challenges are, first, to identify a necessary canon of functions for a system to be considered alive, and second, to reconstitute these respective modules in vitro. When using proteins as obvious candidates, it appears that not only some of their described physiological functions fail to unfold outside the cellular context, but that completely new and unexpected functions are being observed. We put these insights in the context of other recent findings on protein functionality and discuss their potential role in the emergence and evolution of life. While trying to build a cell division system from the bottom up, we encountered several protein functions in vitro which have no obvious role in vivo.Protein functions without clear cellular roles have so far been dismissed as physiologically irrelevant, but this attitude may obstruct a much-needed holistic understanding of biological function.These hidden functions could contribute to the evolutionary fitness of organisms, as they might allow rapid adaptation to changing environments.To understand functional emergence in biological systems, a more quantitative definition of the context-dependent term function is overdue, and computational and experimental methods to identify them need to be developed.A registry of functions, regardless of their physiological relevance, should be established, providing an overview of fundamental biological functions.