Every cell in the body relies on a microscopic postal service to sort and deliver proteins to the right internal compartments, and a protein complex called ESCPE-2 is one of the key workers on that sorting line whose job description has remained largely unknown. This project addresses a fundamental gap in cell biology: how ESCPE-2 physically reshapes membranes to sort cargo. While its partner complex ESCPE-1 is well understood, ESCPE-2’s structure and mechanism have been a black box. The researcher will use advanced cryo-electron tomography to watch ESCPE-2 at work inside living neurons, capturing the first high-resolution images of the tubules it forms to move proteins between compartments. This is fundamental science with no immediate practical application. Understanding how cells organise their internal traffic, however, has historically been essential for grasping what goes wrong in diseases where protein sorting fails—such as certain neurodegenerative disorders. A structural blueprint of ESCPE-2 could eventually help researchers pinpoint where that machinery breaks down, opening routes for future therapeutic intervention. For now, the immediate payoff is a clearer picture of one of the cell’s most basic logistical operations.
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Endosomal trafficking governs protein sorting between subcellular compartments. Sorting nexin (SNX)-BAR proteins are central to this process, sharing a common architecture and membrane-remodelling ability, despite diverse cargo specificity. While ESCPE-1 (SNX1–SNX5) has been well characterised, ESCPE-2 (SNX4–SNX7) remains poorly understood. This PhD project aims to elucidate the structural and biochemical mechanisms by which ESCPE-2 drives membrane tubulation, regulates cargo trafficking, and coordinates with the wider endosomal network. Preliminary in vitro studies established ESCPE-2’s ability to tubulate liposomal membranes under defined lipid compositions, protein concentrations, and reaction conditions. Cryo-electron tomography (cryoET) revealed tubulation in both the presence and absence of sortilin cargo peptides, and preliminary structures of tubulated liposomes have been solved. Building on this, advanced cryoET approaches, including in situ cryoET in i3 neurons and cryo-focused ion beam (FIB) milling for thicker cells, to visualise ESCPE-2-mediated tubules in their native environment, will be implemented. Complementary fluorescence microscopy will map spatial and temporal dynamics, while biochemical assays will probe interactions with ESCPE proteins and other endosomal sorting complexes. The overarching goal is to provide a high-resolution structural and mechanistic framework for ESCPE-2-mediated endosomal sorting, advancing understanding of membrane trafficking regulation and its implications in disease.
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