Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions

The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome.