Limitations of Induced Folding in Molecular Recognition by Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins exist and function without well‐defined three‐dimensional structures and are common in proteomes where they carry out essential functions. Herein, evidence for their lack of structure and the major functional benefits that this confers, are surveyed. An example is Tβ4, a sequence that is disordered until it binds to G‐actin, when it adopts an ordered conformation (see picture). Intrinsically disordered proteins (IDPs) exist and function without well‐defined three‐dimensional structures, thus they defy the classical structure–function paradigm. These proteins are common in proteomes, and they carry out essential functions often related to signalling and regulation of transcription. Herein, the experimental evidence for their lack of structure and the major functional benefits that structural disorder confers, are surveyed. It is shown that IDPs often function by molecular recognition, in which either short motifs, or domain‐sized disordered segments are used for partner recognition. In both cases, the binding segment undergoes induced folding and it attains an ordered structure. This folding‐upon‐binding scenario suggests that the function of IDPs can be interpreted in terms of the static structural view of the classical paradigm. New developments in the field, however, suggest that folding upon binding is limited, and many IDPs preserve a significant level of disorder in the bound state, a phenomenon termed fuzziness. In addition, IDPs may structurally adapt to different partners with different functional outcomes, resulting in promiscuity in function termed moonlighting. It is suggested that a new model describing the structure–function relationship of IDPs has to encompass such structural and functional promiscuity inherent in the disordered state of IDPs.