Every second, the Golgi apparatus inside your cells must sort thousands of newly made proteins to the right destinations—and no one knows exactly how it does this. These proteins make up 27% of the cell’s total protein mass, yet the molecular rules that guide their sorting remain a black box. Recent evidence suggests that the physical environment inside the Golgi—its lipid composition, acidity, and calcium levels—plays a decisive role. This project will map that environment for the first time. Using advanced single-molecule light field microscopy, the researchers will track individual proteins as they move through the secretory pathway, measuring their speed, diffusion patterns, and the local membrane conditions they encounter. They will then identify which protein features allow some to navigate this landscape while others get held back, and how the cell actively shapes that landscape. This is fundamental science. It does not promise an immediate cure or a new product. But understanding how cells sort proteins is essential for biotechnology—where engineered proteins must be efficiently secreted—and for diseases like diabetes, where protein trafficking goes awry. Past work on similar cellular machinery has already led to drugs that control cholesterol and insulin secretion.
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The Golgi apparatus plays a crucial role in organising and sorting newly synthesised proteins to their designated locations within the cell. While these proteins represent 27% of the total protein composition of the cell by mass, the molecular sorting mechanisms remain unknown. It has recently become clear that delivery of proteins to the cell surface and extracellular space is dependent on the biophysical environment of sub-domains within the Golgi. This biophysical environment encompasses the properties and composition of the lipids surrounding sub-cellular organelles as well as the ions and pH of the lumen inside. Our proposal aims will investigate the fundamental molecular determinants of protein sorting through the Golgi apparatus in living cells by combining advanced microscopy techniques with molecular biology methodologies. Firstly, our proposal will create a comprehensive biophysical map of the secretory pathway. Using a combination of kinetic trafficking assays and cutting-edge single-molecule light field microscopy (SMLFM), we will track the biosynthetic sorting of proteins through this pathway, examining their kinetics, diffusion dynamics, and local membrane organisation. Secondly, we will identify the intrinsic properties of proteins that enable them to navigate this biophysical landscape. Lastly, we will investigate the mechanisms underlying the generation and modulation of the biophysical landscape by the cell itself. Exploring the impact of physiological factors such as lipid composition, pH, and calcium ions on protein secretion, we aim to unravel the intricate interplay between protein-lipid interactions and cellular sorting processes, offering invaluable insight into both biotechnology and disease treatment.
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