Exploring the physiochemical principles of formation and function of mesoscale bio-macromolecular clusters

• Applicant: Mrityunjoy Kar, Ph.D.
• Subject Area: Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562384767

Numerous biomacromolecules, including the FET family of RNA binding proteins such as Fused in Sarcoma (FUS), are known to form concentration-dependent, heterogeneous mesoscale clusters and condensates. These structures are integral to various physiological processes, including cellular fitness, transcription, gene regulation, DNA damage repair, cell division, autophagy, skin barrier formation, and immune signaling. Conversely, their aberrant formation is linked to pathological conditions like cancer, neurodegeneration, and infectious diseases. The specific mechanisms by which sequence-coded interactions and nanoscale biomacromolecular information influence the formation of mesoscale clusters and condensates are, at present, still largely unexplored. The proposed research program, therefore, aims to uncover the physicochemical principles governing the formation and size-dependent functions of these clusters and condensates through a detailed methodology structured around the following key objectives: 1. Investigate the sequence-driven determinants of FET proteins in mesoscale cluster formation: This objective aims to decode the fundamental principles governing the formation of mesoscale clusters of FET proteins, particularly how protein structure - determined by intramolecular and intermolecular homotypic (protein-protein) interactions - affects cluster formation. 2. Examine the influence of RNA in mesoscale cluster formation of FUS: This objective aims to determine how FUS interacts with RNA to form mesoscale clusters, focusing on the physicochemical principles that guide these interactions and the impact of intermolecular heterotypic interactions with RNA on cluster formation. 3. Establish the relationship between the size and function of biopolymeric mesoscale clusters: This objective seeks to correlate the size of mesoscale clusters to their functions, using an in vitro transcription system to explore how variations in cluster size affect their biological activity and functionality.

• DFG Programme: Research Grants