Intrinsically Disordered Proteins

Abstract

Abstract Intrinsically disordered proteins (IDPs) represent a growing category of proteins, especially in the eukaryotic proteomes. They are linked to a wide variety of biological functions, including those which are commonly impaired in cancer and neurodegenerative diseases. Since IDPs by definition do not adopt a well‐defined native structure in solution but exist as an ensemble of rapidly interconverting conformations, their structural characterisation is highly challenging. However, a large body of evidence accumulated mainly through nuclear magnetic resonance spectroscopy and small‐angle X‐ray scattering techniques indicates that IDPs are far from the statistical random coil polypeptide chains such as chemically denatured proteins, but exhibit a rich diversity of transient local and long‐range structural propensities. Such structural preferences are likely to be of functional importance and may be considered as potential drug targets. Key Concepts: A large proportion of proteins, especially in eukaryotic proteomes, do not adopt a well‐ordered structure in near‐physiologic conditions. The classical tenet of biochemistry, the so‐called ‘structure–function paradigm’, that proteins need to have a well‐ordered structure to be functional, presents a restricted view. Instead, a wide variety of proteins from highly structured to almost completely unstructured ones play functional roles in biological systems. Intrinsically disordered proteins play crucial roles in cellular processes as diverse as signalling, cell cycle control, molecular recognition, transcription, replication and chaperoning. Accordingly, they are closely linked to pathologic states such as cancer and neurodegenerative disorders. Biophysical techniques, in particular NMR spectroscopy, SAXS and single‐molecule fluorescence measurements, provide detailed insight into the conformations populated by intrinsically disordered proteins. The intrinsically disordered proteins are not like statistical coil‐like polypeptide chains, but show local and even long‐range structural preferences. The ‘ensemble view’ of intrinsically disordered proteins resolves the ‘reconciliation problem’, the apparent inconsistence between their coil‐like hydrodynamic behaviour and presence of secondary and even tertiary contacts. A more‐detailed structural knowledge of intrinsically disordered proteins might provide a basis for rational drug design against them.