“Designing Protein Coacervates as Synthetic Organelles for Programmable Control of Cell Behavior”
See more of Dr. Good's research on his website: The Good Lab
"A grand challenge in the field of cellular engineering is achieving predictable control of cell decision-making. To attain this, we must be able to integrate facile controllers within living systems that provide modular regulatory control over subcellular processes and cell functions. Cells subcompartmentalize biochemical processes to enhance the rate and fidelity of these reactions. Numerous regulatory systems are partitioned to spatially distinct membraneless compartments including nucleoli, nuclear speckles, stress granules and germ granules. These mesoscale structures or biomolecular condensates are heterotypic assemblies often comprised of intrinsically disordered proteins (IDPs) and RNAs. Designer condensates, constructed from single proteins and which display controllable size, cargo capacity and controlled release functions promise a new strategy to deploy control systems in cells. Using a variety of model disordered polypeptides, we have constructed synthetic organelle platforms that can be genetically encoded in cells and which enable dynamic sequestration-release of native enzymes to control cell behaviors on-demand. We determined the sequence rules for homotypic assembly of the RGG domain of the germ granule protein LAF-1, and re-engineered this protein to assembly and disassemble in response to enzymatic, optical and thermal stimuli. We have biophysically characterized these synthetic coacervates in vitro, in protocells and in living cells and achieved selective concentration of targets to these designer compartments via coiled coil interaction motifs embedded within the disordered scaffold and specific target protein. Recently we discovered principles governing the selectivity of IDP coacervation and identified pairs of polypeptides capable of forming discrete condensed phases in vitro and in living cells. Further we have expanded our delivery strategies both to deploy these minimal organelle systems in a variety of cell types, and for non-genetic uptake of coacervates as signaling hubs. Designer synthetic organelles hold great promise both as linkable modules to create synthetic life and as versatile protein circuits to program cellular information processing."
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