Our particular focus is the rhomboid-like superfamily of membrane 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.
Our experimental approaches include genetics, cell biology, biochemistry and structural biology, mainly in mammalian cells but also with a variety of model systems including mice, Drosophila 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. We have also recently started to explore the use of rhomboid-like proteins as tools for cellular engineering of other membrane proteins.
Funding Notes
4 Year PhD Prize Studentships cover full University fees, a tax free enhanced stipend of ~£24,305 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
- Lu, F., Zhao, H., Dai, Y., Wang, Y., Lee, C. H. & Freeman, M. (2024) Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals. Mol Cell 84, 2152–2165.e5. [10.1016/j.molcel.2024.04.025] [PMC11248996]
- Dulloo, I., Tellier, M., Levet, C., Chikh, A., Zhang, B., Blaydon, D. C., Webb, C. M., Kelsell, D. P. & Freeman, M. (2024) Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway. Mol Cell 84, 277–292.e9. [10.1016/j.molcel.2023.12.012] [PMC7618786]
- Tang, S., Beattie, A. T., Kafkova, L., Petris, G., Huguenin-Dezot, N., Fiedler, M., Freeman, M. & Chin, J. W. (2022) Mechanism-based traps enable protease and hydrolase substrate discovery. Nature 602, 701–707. [10.1038/s41586-022-04414-9] [PMC8866121]
- 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. & Freeman, M. (2021) Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation. Mol Cell 81, 4784–4798.e7. [10.1016/j.molcel.2021.10.025] [PMC8657799]
