Evolving concepts of the protein universe

The protein universe is the collection of all proteins on earth from all organisms both extant and extinct. Classical studies on protein folding suggested that proteins exist as a unique three-dimensional conformation that is dictated by the genetic code and is critical for function. In this perspective, we discuss ideas and developments that emerged over the past three decades regarding the protein structure-function paradigm. It is now clear that ordered (active/functional) and disordered/denatured (and hence inactive/non-functional) represent a continuum of states rather than binary states. Some proteins can switch folds without sequence change. Others exist as conformational ensembles lacking defined structure yet play critical roles in many biological processes, including forming membrane-less organelles driven by liquid-liquid phase separation. Numerous diverse proteins harbor segments with the potential to form amyloid fibrils, many of which are functional, and some possess prion-like properties enabling conformation-based transfer of heritable information. Taken together, these developments reveal the remarkable complexity of the protein universe.