Upon binding to their ligands, transmembrane receptors are internalised from the plasma membrane into sorting endosomes where they can either be targeted for degradation in lysosomes or for recycling back to the cell surface. In this way, endosomal sorting controls the cell surface proteome and the cell’s capacity to react to external stimuli. But while cargo sorting in endosomes is a general requirement for all cells, it is further modulated in polarized cells to tune their signalling capabilities. For instance, to properly function, neurons need different neurotransmitter receptors in their axons rather compared to dendrites. This requires the selective loading of axon-specific receptors into the specific endosomes that are targeted to the axon.
This project aims at understanding molecularly how receptor sorting is tuned by cell polarity to achieve complex patterns of signalling during development.
The successful applicant will capitalize on the recent technological breakthrough by the host lab in collaboration with the Baker lab and James Manton, namely the direct imaging of endosomal sorting of endogenous receptors in live cells by combing multispectral imaging with de-novo designed fluorescent minibinders. You will now combine this technique with methods previously established in the host lab to engineer cell shape and/or polarity using micropatterns and/or de-novo designed protein polymers. By quantitatively measuring how the dynamics of cargo sorting is affected in space and time by cell shape and/or polarity, you will be able to establish how polarity tunes receptor sorting. We will then investigate how this is perturbed by deletion/depletion of sorting/polarity machineries to reach a molecular understanding of this process.
This project would suit biology students with strong skills in microscopy and image analysis. Biochemistry skills would be a plus.
References
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Watson, J.L., Krüger, L.K., Ben-Sasson, A.J., Bittleston, A., Shahbazi, M.N., Planelles-Herrero, V.J., Chambers, J.E., Manton, J.D., Baker, D., Derivery, E. (2023)
Synthetic Par polarity induces cytoskeleton asymmetry in unpolarized mammalian cells
Cell 186(21): 4710-4727
Watson, J.L., Aich, S., Oller-Salvia, B., Drabek, A.A., Blacklow, S.C., Chin, J., Derivery, E. (2021)
High-efficacy subcellular micropatterning of proteins using fibrinogen anchors
J Cell Biol 220(2): e202009063