Linking Biomolecular Condensates to Disease and Therapeutic Development

Abstract

The cell is compartmentalized into membrane-bound and membraneless organelles that organize and regulate key cellular functions. Over the past decade, growing evidence supports the notion that membraneless organelles, called biomolecular condensates, compartmentalize biomolecules – proteins and nucleic acids – involved in shared cellular processes through a biophysical process called phase separation. Biomolecular condensates have distinct physicochemical properties dependent on the molecular features and interactions of constituent biomolecules. Diseaseassociated mutations in individual biomolecules that compose condensates can alter condensate physicochemical properties. In addition, key drug targets have been identified as components of condensates. This thesis examines biomolecular condensates in disease and therapeutic development. We find that condensate-promoting features in condensate-forming proteins can be mapped and leveraged to build a resource cataloging mutations that likely contribute to condensate dysregulation in human diseases (Banani et al., 2022). Pathogenic mutations in condensate-promoting features span diverse disease classes across both Mendelian diseases and cancers. FDA-approved small molecule therapeutics interact with condensates, selectively partitioning into some condensates and not others (Klein et al., 2020). Selective partitioning of small molecules has broad implications for drug therapeutic activity and resistance. These findings demonstrate the need to integrate condensate-based models in our study of disease and therapeutic development – an effort which will generate novel pathogenic mechanistic hypotheses and improved drug design for human diseases.