Elucidating the physical mechanisms of membrane fission

Snead, Wilton Thomas
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Cellular membranes must be dynamically remodeled to facilitate essential cellular functions like membrane trafficking, cell division, and organelle biogenesis. However, membranes are resistant to the deformations required to shape them and divide them into multiple compartments, the process known as membrane fission. Therefore, proteins must provide significant energetic contributions to drive these processes. For example, helical protein scaffolds that assemble at membrane surfaces are thought to force membranes to adopt the curved geometry of the scaffold. In another example, hydrophobic portions of proteins that insert shallowly into membranes are thought to expand the area of one membrane monolayer relative to the opposite monolayer, causing the membrane to take on curvature and undergo fission. In my dissertation work, I have discovered another mechanism of membrane fission that relies on protein crowding. Specifically, molecular collisions among proteins densely attached to membrane surfaces generates significant steric pressure that, if not balanced on the opposite membrane monolayer, can drive membrane curvature and spontaneous membrane fission. My work has revealed that steric pressure can drive membrane fission regardless of the hydrophobicity of membrane insertions, arguing against the role of hydrophobic insertions in membrane fission. In further support of the protein crowding mechanism, I find that disordered protein domains, which occupy greater areas on the membrane surface in comparison to globular proteins of similar mass, are among the most potent drivers of membrane fission. I also report the surprising finding that the assembly of helical protein scaffolds at membrane surfaces locally amplifies crowding among disordered domains found naturally in many scaffolding proteins. The resulting acute increase in steric pressure drives membrane fission with greater potency compared to non-assembling proteins. My work thereby reveals a synergistic collaboration between structured proteins that assemble at membrane surfaces and disordered proteins that generate steric pressure. More broadly, my results challenge the paradigm that dedicated, structured protein machines are required for membrane fission, suggesting instead that any protein may contribute to fission by generating steric pressure. As such, my findings suggest how early cells may have achieved membrane fission before the evolution of dedicated fission proteins.