The two faces of Janus: functional interactions and protein aggregation

Protein aggregation constitutes a constant threat for the living cell as is demonstrated by the several pathologies in which the mechanisms to prevent it fail. It is therefore a question of increasing importance to understand in detail the defence strategies. Here we discuss how molecular interactions can represent a general strategy to prevent aggregation. This view generalizes the more specific paradigm that suggests a competition between folding and aggregation, and allows to include both intrinsically unfolded proteins and proteins that aggregate also under native conditions. We analyze the factors that influence the balance between the two competing pathways and suggest new perspectives to increase our understanding of misfolding pathologies.

► We discuss how protein function is the competing pathway of protein aggregation. ► This concept generalizes the accepted idea that aggregation competes folding. ► Functional molecular interactions are at the basis of the cellular organization. ► We suggest that the cellular crowding is structured by functional interactions.