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Leeds/AstraZeneca CASE: Structural mechanisms of fibroblast growth factor receptor signalling at the membrane interface


Project Description

Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that play key roles in embryo development, tissue remodelling, wound healing, and cancer. An enduring enigma of FGFR signalling is the question of how the output (activation of a specific signalling module, e.g. Raf-Mek-Erk) is selected based on the nature and level of the input signal (binding of a particular FGF variant). Despite extensive characterisation of extracellular ligand binding and intracellular kinase domain activation and inhibition using structural biology, the role of the lipid environment in allosterically modulating signal transduction across the membrane remains poorly understood; however it is clear that it must exert a major influence on signalling outcomes.
In this project, you will combine structural biology and biophysical (native MS & structural proteomics) approaches together with mutagenesis, cell biology and imaging to elucidate key mechanistic features of the interaction between the kinase domain, juxtamembrane region and membrane lipids, and determine how these interactions influence downstream signalling through the constitutively-bound FGFR adaptor protein, FRS2.
Specifically, you will:
1. Characterise the interaction between membrane lipids and the JM-KD of FGFR3 using NMR in a membrane-mimetic system (nanodiscs and/or styrene maleic acid lipid particles (SMALPs))
2. Use native mass spectrometry (MS) & structural proteomics methods pioneered in Leeds, including ion-mobility (IM-MS), hydrogen-deuterium exchange (HDX-MS) and fast photochemical oxidation of proteins (FPOP), to provide orthogonal structural mapping of lipid-protein interactions as well as characterisation of the lipid composition around natively-expressed FGFRs.
3. Elucidate the interaction between FGFR3 JM-KD and the membrane-anchored adapter protein FRS2 using NMR, MS and cell-based imaging approaches.
The student will benefit from the Astbury Centre’s world-leading structural biology infrastructure, with >£20M of recent investment, with specialist equipment including 950 MHz NMR, top-end Orbitrap protein mass spectrometry and Titan Krios cryo-EM.
Leeds and AZ have synergistic expertise in FGFR cell biology and structural biology and together can provide cutting-edge infrastructure to the project and provide a unique competitive advantage to the student, with a highly distinctive research experience that can be effectively levered for future career opportunities, whether academic or industrial.

Funding Notes

This project is funded by a BBSRC CASE PhD studentship for 4 years. The industrial partner is AstraZeneca (Cambridge).

References

1. Farrell B & Breeze AL (2018) Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting. Biochem Soc Trans 46, 1753-1770. doi: 10.1042/BST20180004
2. Patani H, et al. (2016) Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use. Oncotarget Mar 16. doi: 10.18632/oncotarget.8132
2. Klein T, et al. (2015) Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase. Nat. Commun. 6, 7877. doi: 10.1038/ncomms8877
3. Bunney T et al. (2018) Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System. Structure 26, 446-458. doi: 10.1016/j.str.2018.01.016

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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