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Understanding Movement and Mechanism in Molecular Machines (MACMILLANF1U19SF)


Project Description

We study the architecture and functional dynamics of membrane proteins, especially many medically relevant membrane transport systems. There is increasing evidence that membrane proteins do not act alone, but that they are organised as nanomachineries which function through the concerted action of individual components with high precision and specificity observed in both time and space. We are seeking to unravel the principles underlying the architecture and dynamics of these protein nanomachineries as well as their function. Our experimental approach focuses on the use of magnetic resonance techniques specifically Electron Paramagnetic Resonance (EPR) and Nuclear Magnetic Resonance (NMR) spectroscopy in combination with molecular biological, and biochemical approaches.

This PhD project will study a specific divalent anion sodium symporter (DASS) transporter VcINDY. In eukaryotes, reducing cytoplasmic citrate modulates the energy homeostasis of cells and induces caloric restriction like benefits. Citrate enters the cytoplasm through the DASS transporter family. Disruption of DASS function can increase lifespan, protect against insulin resistance and adiposity, and inhibit cancer cell proliferation. Thus, human DASS transporters are prime drug targets to treat numerous chronic diseases and promote healthy ageing. However, DASS transporters are highly dynamic and the development of DASS inhibitors relies on understanding the distribution of conformational states. Recent structural studies have proposed large scale conformational changes and we aim to probe the functional dynamics of this protein using a combination of state-of-the-art magnetic resonance techniques as well as techniques to purify and stabilise the protein using novel SMA lipid particles.


Project start date: October 2019
Mode of Study: Full-time
Entry requirement: Minimum UK 2:1.
Acceptable first degree: Chemistry, Biochemistry, Biophysics, Physics or related

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at View Website.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.

The project may be filled before the closing date, so early application is encouraged.

References

i) Mullen, A.; Hall, J.; Diegel, J.; Hassan, I.; Fey, A.; MacMillan, F. Membrane transporters studied by EPR spectroscopy: structure determination and elucidation of functional dynamics. Biochem. Soc. Trans. 2016, 44, 905–915.
ii) Mulligan, C.; Fitzgerald, G. A.; Wang, D. N.; Mindell, J. A. Functional characterization of a Na+-dependent dicarboxylate transporter from Vibrio cholerae. J. Gen. Physiol. 2014, 143, 745– 759
iii) Lee, S. C.; Knowles, T. J.; Postis, V. L. G.; Jamshad, M.; Parslow, R. A.; Lin, Y.-P.; Goldman, A.; Sridhar, P.; Overduin, M.; Muench, S. P.; et al. A method for detergent-free isolation of membrane proteins in their local lipid environment. Nat Protoc 2016, 11, 1149–1162
iv) Oluwole, A. O., Danielczak, B., Meister, A., Babalola, J.O., Vargas, C., and Keller, S.; Solubilization of Membrane Proteins into Functional Lipid-Bilayer Nanodiscs Using a Diisobutylene/Maleic Acid Copolymer. Angew. Chem. Int. Ed. 2017, 56, 1919 –1924


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