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Rhomboid-like proteins: from molecular principles to their role in human disease


   Sir William Dunn School of Pathology

  Prof M Freeman  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

The questions we address deal with the molecular mechanisms that underlie signalling between cells, and cellular responses to stress. These processes are implicated in multiple human diseases including cancer, neurodegeneration, inflammation and infection, and our work has wide potential medical relevance.

Our particular focus is the rhomboid-like superfamily of proteins. We were the first to discover rhomboids, and we proved that they were novel intramembrane proteases, conserved across evolution, and that they controlled growth factor signalling. Since then, the rhomboids have been implicated in many biological processes including, for example, growth factor activation, neurodegeneration, mitochondrial function, host cell invasion by parasites and bacterial physiology.

More recently we have become interested in the much wider superfamily of rhomboid-like proteins, the majority of which are not proteases. We have studied a few examples and have uncovered roles in controlling the cellular fate of membrane proteins. We study the cell biology, biochemistry and structural biology of rhomboid-like proteins, using a variety of systems including human cells, mice, and yeast. Although our main effort is aimed at understanding fundamental biology of the rhomboid-like superfamily, we are also actively pursuing the potential medical significance of our basic discoveries.


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

Tang, S., Beattie, A. T., Kafkova, L., Petris, G., Huguenin-Dezot, N., Fiedler, M., Freeman, M., and Chin, J. W. (2022). Mechanism-based traps enable protease and hydrolase substrate discovery. Nature 602, 701-707.
Dulloo, I., Atakpa-Adaji, P., Yeh, Y. C., Levet, C., Muliyil, S., Lu, F., Taylor, C. W., and Freeman, M. (2022). iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2. Nat Commun 13, 1257.
Grieve, A. G., Yeh, Y. C., Chang, Y. F., Huang, H. Y., Zarcone, L., Breuning, J., Johnson, N., Stříšovský, K., Brown, M. H., Parekh, A. B., and Freeman, M. (2021). Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation. Mol Cell 81, 4784-4798.e7.
Adrain, C., Zettl, M., Christova, Y., Taylor, N., and Freeman, M. (2012). Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335, 225-228.

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