How do transport vesicles find the correct organelle to fuse with?
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A fundamental feature of eukaryotic cells are the pathways of transport vesicles that move proteins between intracellular organelles. These membrane trafficking pathways are essential for secretion, uptake of nutrients, and the regulation of signalling pathways. The same pathways are exploited by many pathogens to enter cells and then replicate. Our lab studies how specificity is achieved during membrane traffic: how does a transport vesicle that buds from one location find the correct destination organelle?
Nowhere is this specificity problem more acute than at the Golgi apparatus, a central sorting system that exchanges vesicles between multiple sources. Our lab has discovered that vesicles arriving at the Golgi are captured by ‘tentacles’ formed by long coiled-coil proteins called golgins (Wong and Munro 2014). Moving a single golgin to a different organelle is sufficient cause capture of its target vesicles at this ectopic location. Different golgins can capture vesicles coming from different parts of the cell. These findings provide a unique opportunity to isolate specific classes of transport vesicles and understand how targeting specificity is encoded in membrane trafficking pathways. Our recent work has identified a linker protein that attaches a class of transport vesicles to two of the golgins (Shin et al. 2017), but for most golgins their mechanism of action is still to be revealled (Muschalik and Munro 2018).
The PhD project is to investigate the mode of action of the golgins that capture the vesicles that carry newly-made secreted proteins from the endoplasmic reticulum to the Golgi. This will involve using both biochemistry and in vivo methods such as proximity biotinylation (BioID) to identifying the proteins on the vesicle that bind the golgin, and to investigate how these interactions impart specificity. The project will provide the opportunity to learn and apply a wide range of cell biological methods including CRISPR/Cas9 genome engineering, BioID, proteomics, high-resolution microscopy, live cell imaging and electron microscopy.
Muschalik N. and Munro S. (2018)
Current Biology, 28, R374-R376.
Shin, J.H, Gillingham, A.K., Begum, F., Chadwick, J. and Munro S. (2017).
TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi.
Nature Cell Biology 19, 1424-1432.
Wong, M. and Munro, S. (2014)
Membrane trafficking. The specificity of vesicle traffic to the Golgi is encoded in the golgin coiled-coil proteins.
Science, 346, 1256898.