Regulation and Function of Biomolecular Condensate

Project Summary A fundamental question in cell biology is how this crowded space can be organized to enable the control of biochemical processes and reactions in space and time. Biomolecular condensates have emerged as a potential universal solution to how activities and functions are organized within cells. Condensates by nature are formed via collective interactions between biomolecules which together form concentrated assemblies. These collective biochemical interactions govern both condensate regulation and function within cells. The interface of the condensate with the cytosol (interfacial surface) has emerged as a critical molecular determinant for condensate regulation, and function. Biological Pickering agents absorb the interfacial surface of condensates and offer a versatile solution for how cellular functions can be compartmentalized. As interest in biomolecular condensates as an organizing principle in the cell has increased, so have the criticisms of the quality of evidence supporting the biological significance of condensates in native cells. To overcome these valid criticisms a key challenge moving forward for the field is the development of technical approaches to measure and manipulate the collective interactions within these assemblies in native cells. The molecular mechanics that underpin condensate regulation, dynamics, and function in native cells is not well understood. During C. elegans embryogenesis, RNA granules called P granules undergo a dramatic stereotyped polarization within the zygote. Using P granule as a model condensate this proposal aims to define the core biochemical principles that underpin the spatial and temporal regulation of P granule polarization. The goals of this proposal are to 1) identify key biochemical determinants that facilitate P granule assembly 2) define the molecular mechanism by which DYRK kinase regulate P granule disassembly 3) define the biochemical mechanism by P granule assembly and disassembly is spatially regulated 4) determine the biochemical mechanism by which biological Pickering agents are removed from the interfacial surface of P granule 5) define the molecular mechanics that underpin the kinetic arrest of P granules. To accomplish these goals, we will use a multifaceted approach that includes biochemistry, cell biology, and genetics. Leveraging our unique in vivo and in vitro assays we will define the collective biochemical grammar that facilitates the regulated assembly and disassembly of P granules.