Avigail Baruch Leshem

Abstract Condensates formed via liquid-liquid phase separation (LLPS) provide a chemically versatile environment for catalysis through dynamic molecular interactions. We present designed biomolecular condensates, formed by LLPS of minimalistic histidine-containing peptides, catalyzing ester hydrolysis with two distinct mechanisms. Zn2+-dependent condensates activate a coordinating water molecule at the active site, formed by Zn2+-histidine coordination, enabling nucleophilic attack.

Introduction Click to copy section linkSection link copied! The compartmentalization of biochemical reactions within spatially distinct cellular environments is a hallmark of life, allowing for precise spatiotemporal regulation of complex processes. (1) For example, ATP synthesis occurs within mitochondria, leveraging the proton gradient to drive energy production, while proteolysis is compartmentalized in lysosomes, which isolates degradative enzymes to ensure cellular homeostasis.

1 Introduction Cellular liquid–liquid phase separation (LLPS) is the underling process that governs the formation of homotypic or heterotypic biomolecular condensates.[1] Cellular homotypic condensates including GTPase GIT[2] and tau protein[3] are formed by associative interactions between a single intrinsically disordered protein (IDP).