Design Principles of Size-Control of Organelles Growing in a Shared Pool of their Building Blocks

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ABSTRACT Living cells contain a variety of distinguishable parts called organelles which have characteristic sizes and specific functions. These organelles grow in a shared pool of their respective building blocks, and are remarkably able to maintain their structure despite a rapid exchange of their building blocks. This prompts a question: how are the sizes of organelles growing in a shared pool of building blocks actively controlled by the cell? Years of biochemical experiments have revealed a plethora of proteins involved with these structures, yet, due to the high-dimensionality of the variables involved, how they all work together to create properly-sized organelles is still not well understood. Mathematical modeling and simulations, thus, provide an exciting avenue to tackle these questions, with the added benefit of identifying key tunable knobs for biochemists to run streamlined experiments. Over the last few years, using these techniques on organelles like actin cable and flagellum, I identified that a negative feedback to the size, mediated by a diminishing pool of building blocks or key accessory proteins specific to the organelle, was critical in controlling the size of a growing organelle. Significantly, the key experimental knobs that we suggested, have since been used to test the predictions of my quantitative models. My results enabled us to understand the design principles for constructing a single structure, yet how competing structures assemble and maintain their sizes while sharing a common pool of building blocks remains an open question. Over the next five years, our goal is to quantitatively analyze the mechanisms used by the cell to share building blocks between competing structures. Proteins involved in disassembly of organelles offer a solution - in addition to disassembling pre-existing structures, they can provide key length-sensing feedback to the size of individual structures sharing a common pool of building blocks. Using simulation schemes and theoretical tools that I pioneered, we will identify discernible signatures of specific disassembly mechanisms, and quantitatively describe their repercussion on the sharing of common resources between different competing structures. Using actin structures and nucleolus as our model systems, we will design theory-driven experiments to verify our predictions with already established collaborations, and use experimentally tunable knobs to discriminate between different mechanisms that cells use to share building blocks between competing structures. A quantitative understanding of molecular mechanisms affecting organelle growth will accelerate the development of new therapies to combat many human neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (abnormalities in actin assembly) and Parkinson’s and Alzheimer’s disease (nucleolus abnormalities).