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Control of metabolite transport into durable protocells and nanoreactors


Project Description

Protocells (or nanoreactors) are seen as a stepping-stone to understanding the origin of life and are being developed to generate novel cell-like biotechnologies. They are typically vesicles made from phospholipids, which have a short lifespan. In this project you will use principles of synthetic biology to enhance the stability of protocells by creating hybrid bionic systems that combine advantages of lipid and polymer vesicles. Incorporation of membrane proteins will provide essential metabolite transport into (or out of) the vesicle lumen as biochemical signals and reaction substrates. Such systems will have broad-ranging applications, including development of ultrasmart metabolite-responsive drug delivery systems for treatment of diseases such as cancer.

You will build on recent advances in hybrid vesicles as a durable membrane protein reconstitution system: we recently demonstrated a tenfold increase in functional lifetime of a respiratory enzyme (cytochrome bo3) compared to conventional proteoliposomes. This project will focus on metabolite transporters for essential substrate transport and concentration inside vesicle nanoreactors. Membrane proteins for generating proton motive forces of opposite polarities across the hybrid vesicle membrane (cytochrome bo3; pyrophosphatases) will be used. These will be coupled with proton symporters (GalP) and antiporters (AceI) to concentrate their substrates inside the vesicles. Expertise in a broad range of transporter proteins is available in the supervisory team.

You will learn skills in expression, purification, reconstitution and functional characterization of membrane proteins. Advanced biophysical characterization techniques including confocal microscopy and possibly cryo-TEM will be applied to gain detailed insights into the behaviour of these proteins in hybrid membranes.

Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2020:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference and research funding

Requirements:
At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.

EU candidates require 3 years of UK residency to receive full studentship

Not all projects will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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References

Seneviratne R., Khan S., Moscrop E., Rappolt M., Muench S.P., Jeuken L.J.C. and Beales P.A.; A reconstitution method for integral membrane proteins in hybrid lipid-polymer vesicles for enhanced functional durability. Methods 147, 142 – 149 (2018).

Beales P.A., Khan S., Muench S.P. and Jeuken L.J.C.; Durable vesicles for reconstitution of membrane proteins in biotechnology. Biochem. Soc. Trans. 45(1), 15-26 (2017).

Khan S., Li M., Muench S.P., Jeuken L.J.C. and Beales P.A.; Durable Proteo-Hybrid Vesicles for the Extended Functional Lifetime of Membrane Proteins in Bionanotechnology. Chem. Commun. 52, 11020 - 11023 (2016)

Nam J., Vanderlick T.K. and Beales P.A.; Formation and dissolution of phospholipid domains with varying textures in hybrid lipo-polymersomes. Soft Matter 8, 7982-7988 (2012)

Nam J., Beales P.A. and Vanderlick T.K.; Giant Phospholipid/Block Copolymer Hybrid Vesicles: Mixing Behavior and Domain Formation. Langmuir 27 (1), 1-6 (2011)

Booth A., Marklew C.J., Ciani B. and Beales P.A.; In vitro membrane remodelling by ESCRT is regulated by negative feedback from membrane tension. iScience 15, 173-184 (2019).

Stikane, A., Hwang, E.T. Ainsworth, E.V., Piper, S., Critchley, K. Butt, J.N., Reisner, E. Jeuken, L.J.C. (2019) Towards compartmentalized photocatalysis: Multiheme proteins as transmembrane molecular electron conduits, Faraday Discussion, 215, 26-38 DOI:10.1039/C8FD00163D

Oram, J., Jeuken, L.J.C. (2019) Tactic response of Shewanella oneidensis MR-1 towards insoluble electron acceptors, mBio, 10, e02490-18. DOI:10.1128/mBio.02490-18

Li, M., Jørgensen, S.K., McMillan, D.G.G., Krzemiński, L., Daskalakis, N.N., Partanen, R.H., Tutkus, M., Tuma, R., Stamou, D., Hatzakis, N.S., Jeuken, L.J.C. Single enzyme experiments reveal a long-lifetime proton leak state in a heme-copper oxidase, J. Am. Chem. Soc., 137, 6055-16063 (2015).

PARMAR, M., RAWSON, S., SCARFF, C. A., GOLDMAN, A., DAFFORN, T. R., MUENCH, S. P. & POSTIS, V. L. G. Using a SMALP platform to determine a sub-nm single particle cryo-EM membrane protein structure. Biochim. Biophys. Acta 1860, 376–383 (2018).

LI, K.-M., WILKINSON, C., KELLOSALO, J., TSAI, J. Y., KAJANDER, T., JEUKEN, L. J., SUN, Y.-J. & GOLDMAN, A. Membrane pyrophosphatases from Thermotoga maritima and Vigna radiata suggest a conserved coupling mechanism. Nat Commun 7, 13596 (2016).

HASSAN, K, LIU Q, ELBOURNE LDH, AHMAD I, SHARPLES D, NAIDU V, CHAN CL, LI L, HARBORNE SPD, POKHREL A, POSTIS VLG, GOLDMAN A, HENDERSON PJF AND PAULSEN IT (2017). Pacing across the membrane: The novel PACE(AceI) family of efflux pumps is widespread in Gram-negative pathogens. Research in Microbiology, DOI: 10.1016/j.resmic. 2018.01.001.

How good is research at University of Leeds in Chemistry?

FTE Category A staff submitted: 34.40

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

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