Intrinsically Disordered Proteins: The Dark Horse of the Dark Proteome

Abstract A good portion of the ‘protein universe’ embodies the ‘dark proteome’. The latter comprises proteins not amenable to experimental structure determination by existing means and inaccessible to homology modeling. Hence, the dark proteome has remained largely unappreciated. Intrinsically disordered proteins (IDPs) that lack rigid 3D structure are a major component of this dark proteome across all three kingdoms of life. Despite lack of structure, IDPs play critical roles in numerous important biological processes. Furthermore, IDPs serve as crucial constituents of proteinaceous membrane‐less organelles (PMLOs), where they often serve as drivers and controllers of biological liquid–liquid phase transitions responsible for the PMLO biogenesis. In this perspective, the role of IDPs is discussed in i) the origin of prebiotic life and the evolution of the first independent primordial living unit akin to Tibor Gánti's chemoton, which preceded the Last Universal Common Ancestor (LUCA), ii) role in multicellularity and hence, in major evolutionary transitions, and iii), their role in phenotypic switching, and the emergence of new traits and adaptive opportunities via non‐genetic, protein‐based mechanisms. The emerging picture suggests that despite being major constituents of the dark matter, IDPs may be the dark horse in the protein universe.