From Fuzzy to Function: The New Frontier of Protein–Protein Interactions

Conformationally heterogenous or "fuzzy" proteins have often been described as lacking specificity in binding and in function. The activation domains, for example, of transcriptional activators were labeled as negative noodles, with little structure or specificity. However, emerging data illustrates that the opposite is true: conformational heterogeneity enables context-specific function to emerge in response to changing cellular conditions and, furthermore, allows a single structural motif to be used in multiple settings. A further benefit is that conformational heterogeneity can be harnessed for the discovery of allosteric drug-like modulators, targeting critical pathways in protein homeostasis and transcription.