Fuzziness enables context dependence of protein interactions.

Proteins may undergo adaptive structural transitions to accommodate to their cellular milieu and respond to external signals. Modulation of conformational ensembles can rewire the intra- or intermolecular interaction networks and shift between different functional states. Adaptive conformational transitions are associated with protein fuzziness, which enables (a) rewiring interaction networks via alternative motifs, (b) new functional features via allosteric motifs, (c) functional switches upon post-translational modifications, or (d) regulation of higher-order organizations. We propose that all these context-dependent functional changes are intertwined with structural multiplicity or dynamic disorder in protein assemblies and can only be described by stochastic structure-function relationships.