Context-dependent, fuzzy protein interactions: Towards sequence-based insights

Predicting protein interactions in the cellular environment still remains a challenge in the AlphaFold era. Protein interactions, similarly to their structures, sample a continuum from ordered to disordered states, with specific partners in many bound configurations. A multiplicity of binding modes (MBM) enables transition between these states under different cellular conditions. This review focuses on how the cellular environment affects protein interactions, highlighting the molecular mechanisms, biophysical origin, and sequence-based principles of context-dependent, fuzzy interactions. It summarises experimental and computational approaches to address the challenge of interaction heterogeneity and its contribution to a wide range of biological functions. These insights will help in understanding complex cellular processes, involving conversions between protein assembly states, such as from liquid-like droplet state to the amyloid state.