How Hierarchical Interactions Make Membraneless Organelles Tick Like Clockwork

Biomolecular condensates appear throughout the cell, serving many different biochemical functions. We argue that condensate functionality is optimized when the interactions driving condensation vary widely in affinity. Strong interactions provide structural specificity needed to encode functional properties but carry the risk of kinetic arrest, while weak interactions allow the system to remain dynamic but do not restrict the conformational ensemble enough to sustain specific functional features. To support our opinion, we describe illustrative examples of the interplay of strong and weak interactions that are found in the nucleolus, SPOP/DAXX condensates, polySUMO/polySIM condensates, chromatin, and stress granules. The common feature of these systems is a hierarchical assembly motif in which weak, transient interactions condense structurally defined functional units.

Automated summary

Biomolecular condensates are present throughout the cell and serve various biochemical functions. The optimization of condensate functionality relies on a wide range of interactions driving condensation, involving both strong and weak affinities. This is illustrated by examples such as the nucleolus, SPOP/DAXX condensates, and chromatin, where a hierarchical assembly motif of weak, transient interactions condense structurally defined functional units.