@article{Oligomerization:4016,
      recid = {4016},
      author = {Lang, Charles},
      title = {The Role of Protein Oligomerization in Cell Surface  Polarity},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2022-06},
      pages = {141},
      abstract = {A hallmark of biological life is the cell’s apparent  ability to orient itself purposefully in space. This  property is referred to as cell polarity. Cell polarity is  enabled by specific polarity proteins that are  asymmetrically distributed on the cell surface. These  polarity proteins interact within conserved modules to form  biochemical feedback circuits and as result, the  asymmetries they form tend to be self-stabilizing. While  the constituent parts of these circuits are known in many  cell contexts, how they generate self-stabilizing  asymmetries remains only partially understood.	In the first  chapter of this dissertation, I review the current  literature on cell polarity. I discuss three examples of  core polarity modules that stabilize asymmetries through  various feedback loops. These core modules are utilized  across cellular contexts to polarize cells in response to  multiple different inputs and produce different asymmetries  by interacting with different effector proteins. I show  that these core circuits can be abstracted in mass  conserved activator substrate (MCAS) models and review the  insights we have gained from studying theoretical models.  Finally, I discuss the role of protein clustering in core  polarity circuits and show how it enables the  establishment, maintenance, and elaboration of cell  polarities.
	In the second chapter of this dissertation, I  take a theoretical approach to show how protein  oligomerization can modulate the potential for and dynamics  of cell polarization. I show that size-dependent binding  avidity and mobility of membrane-bound oligomers endow  polarity circuits with several key properties. Dynamic  oligomerization and size-dependent membrane binding avidity  confers local positive feedback on the accumulation of  oligomer subunits, which while insufficient by itself,  sharply reduces the amount of additional feedback required  for spontaneous emergence and stable maintenance of  polarized states. Size-dependent oligomer mobility makes  symmetry-breaking and stable polarity more robust with  respect to variation in subunit diffusivities and cell  sizes, and slows the approach to a final stable spatial  distribution, allowing cells to “remember” polarity  boundaries imposed by transient external cues. Given its  prevalence and widespread involvement in cell polarity, I  speculate that self-oligomerization may have provided an  accessible path to evolving simple polarity circuits.
	In  the third chapter, I apply this mathematical model to PAR  protein polarity in the C.elegans zygote. Specifically, I  consider the role of PAR-3 oligomerization in stabilizing  PAR asymmetries. Using fast single molecule imaging, I show  that PAR-3 oligomers are larger on the anterior membrane,  and measure oligomer size-dependent membrane dissociation.  This combination results in PAR-3 more stably associating  with the anterior membrane than the posterior. I further  show that asymmetries in the distributions of PAR-3  oligomers are dynamically maintained and that the  recruitment of new PAR-3 monomers to the cell membrane  exhibits an anterior bias. Using a combination of  mathematical modeling and experiments, I provide evidence  that the combination of feedback on monomer recruitment,  dynamic oligomerization, and avidity effects enables PAR-3  asymmetries to self-stabilize, and that these processes are  in turn regulated by interactions with other PAR proteins  on the anterior membrane. Finally, I show that the  positions of PAR-3 domain boundaries are not encoded by a  reaction diffusion system, and propose instead that  oligomer size-dependent decreases in PAR-3 mobility  effectively preserve arbitrary domain boundaries for the  duration of polarity maintenance. Together, these results  reveal a novel mechanism for stabilizing PAR-3 asymmetries  in the C.elegans zygote.
	In the final chapter, I discuss  the implications of this work and future directions in this  field. I discuss the potential to apply my modeling work to  other polarity systems, the possible sources of feedback on  PAR-3 membrane binding, and the potential and pitfalls of  constructing mathematical models of PAR polarity. Finally,  I outline a potential future project to understand how  PAR-3 asymmetries shape PAR-6/PKC-3 distributions.},
      url = {http://knowledge.uchicago.edu/record/4016},
      doi = {https://doi.org/10.6082/uchicago.4016},
}