Molecular rulers to measure membrane thickness in live cells

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The physicochemical properties of membranes, including membrane thickness, are thought to be crucial for their functions. However, a lack of tools has hindered systematic investigations of membrane thickness in live mammalian cells. We propose here to develop and validate a set of DNA-based molecular rulers to measure membrane thickness in the plasma membrane as well as in internal organelles. These rulers will include hydrophobic belts to allow insertion of the DNA nanostructure into membranes, as well as fluorophores attached at defined distances, allowing quantitative analysis. Rulers designed to probe membranes in the interior of cells will carry SNAP-tag-reactive groups to direct them to SNAP-tag labelled organelle proteins. Using these molecular rulers, we will investigate how cells utilise changes in membrane thickness, for example, in the plasma membrane as they move or divide. This study will be the first time it will have been possible to investigate systematically and quantitatively how and why cells vary membrane thickness in different locations and during different processes.