Two Decades of IDPs; What have we Learned?

The existence of functional, disordered proteins—now termed intrinsically disordered proteins, or IDPs—was recognized about 20 years ago, leading to the now paradigmic concept of folding-upon-binding and the association of disorder with multifarious interactions. Shortly after the initial observations, first Dunker and then others developed computational algorithms to accurately identify disordered regions within protein sequences. The development of disorder predictors coincided with an explosion of gene sequence information due to the Human Genome Project and other large-scale efforts and to the realization that protein disorder is prevalent in all forms of life. Mining of Gene Ontology terms revealed that IDPs are often involved in signaling and regulation, and further analyses revealed their strong associations with human diseases, including neurodegeneration, cancer, diabetes, cardiovascular disease, and others. While awareness of their roles in biology and disease grew rapidly in the 2000s, knowledge of the mechanisms of IDP function progressed at a slower pace. A key discovery, however, was that IDPs can form “fuzzy” complexes with their functional partners, ushering in the disorder-order continuum view of protein “structure”. Systems biology studies showed that IDPs are more tightly regulated in cells than folded proteins and that their dysregulation is likely to alter cellular behavior. Amazingly, the pace of discoveries on IDPs has accelerated during the 2nd decade of the new millennium. IDP sequences can now be decoded in terms of the conformational features of their ensembles, their roles within multi-component assemblies are being cataloged, and IDP-targeted therapeutics are on the horizon. Very recently, the discovery that disordered protein regions mediate liquid-liquid phase separation has revolutionized our understanding of subcellular organization across broad length scales. We will review the evolution of the IDP field over the past two decades and speculate on its current challenges and future directions.