Engineering biomolecular condensate surfaces

The living cell is a complex and synchronized system with compartmentalization across diverse length scales. These individual compartments coordinate countless coinciding biochemical processes to maintain cell function. Many intracellular organelles such as the lysosome and mitochondria are bound by membranes. But cells also contain organelles that are not confined by membranes, which are known as biomolecular condensates. Over the past decade, growing evidence shows that many biomolecular condensates are viscoelastic materials formed from the phase separation of proteins and nucleic acids. The nucleolus is one condensate that is comprised of multiple immiscible liquid-like layers, which help facilitate the biogenesis of the cell's protein synthesizer – the ribosome. How the interfaces between these distinct sub-phases might control transport and reactivity is important for ribosome biogenesis, and how these interfaces might be modulated to control cancer and other diseases, remains unknown. Here we discuss our work to address this challenge, inspired by native proteins that are specifically enriched at the nucleolar periphery. We show that specific physical and chemical design principles can be exploited to design synthetic proteins that exhibit interfacial localization. These engineered nucleolar surfactants are envisioned as a tool to both elucidate key aspects of the biophysics of condensate interfaces and to enable potential modulation of condensate properties and function.