Fuzzy complexes

In the last two decades, intrinsically disordered proteins and, more broadly, proteins with unstructured regions have been increasingly recognized as essential cellular actors, ensuring multiple biological functions both selectively and/or specifically. Such functional properties are remarkably achieved within interaction networks through context-dependent structural rearrangements and transient disorder-to-order transitions. Intriguingly, certain proteins, however, have been found to remain mostly disordered upon binding to their biomolecular partners. This unique behavior is referred to as fuzziness and designates proteins that do not fold into structured elements, exhibiting particularly high conformational heterogeneity and dynamics in their bound state. In this chapter, we discuss the concept, role, impact, and characterization of fuzziness in protein complexes. Despite their lack of structure, different types of fuzzy associations can be discriminated with respect to their binding configuration and mechanism. While fuzzy interactions are involved in regulatory mechanisms and expand the functional catalog of proteins, they are also known to promote pathological pathways, notably in cancer and neurodegenerative diseases. Regarding the targeting of disordered proteins, the druggability of fuzzy interfaces poses great challenges but holds promise in the development of new alternative drug design strategies. Finally, due to their inherent heterogeneous nature, fuzzy complexes are intricate systems to characterize, an issue that can nevertheless be successfully addressed by the combination of biophysical and computational methods.