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Membrane protein folding, the regulation of membrane function and construction of synthetic membrane modules

Integral membrane proteins account for about 30% of all cell proteins and provide the means for vital communication across the membrane in the form of transporters, receptors and signal transducers. Although the number of gene sequences for these proteins is steadily increasing, as is our knowledge of the clinical aspects of these proteins and their demand for drug development, the study of the proteins themselves represents one of the major challenges in modern day molecular biology research.

For a protein to be biologically active it must fold to a specific, three dimensional shape and misfolding can lead to malfunction and disease. In contrast to the large body of information on the folding of water-soluble proteins, remarkably little is known about how membrane proteins fold to their final structures. Such knowledge not only solves a fundamental biological question but also aids the design of membrane proteins and functional membrane vesicles or droplets for Synthetic Biology applications.

Research in my group focuses on membrane protein folding mechanisms and investigations into the role of the membrane lipids in regulating folding and membrane protein activity. We are also interested in membrane protein design and exploiting artificial membranes and protein chemistry in synthetic applications. Several proteins are studied including G protein coupled receptors several transport proteins, including multidrug and ABC transporters. An interdisciplinary approach is used involving time-resolved spectroscopic techniques to measure folding kinetics, calorimetric methods to probe the relevant energetics, computer simulations and modelling, site-directed mutagenesis or chemical modification methods to investigate folding intermediates and manipulation of the lipid environment to control the folding.

Professor Booth's Research Portal 

Paula Booth's group works at the interface of Chemistry and Biology to elucidate the mechanisms by which proteins fold, assemble and communicate within biological membranes. Emphasis is placed on understanding the role of membrane lipids in regulating protein folding and function. Membrane proteins account for about 30% of all cell proteins, and play pivotal roles in life reflected in their domination of drug targets. The group’s research aims to not only solve fundamental questions relating to membrane protein biogenesis and folding, but also to exploit the self-assembly of artificial biomembranes for Synthetic Biology and catalytic applications.

Booth Research Page 

• Harris, NJ, Findlay, HE, Simms, J, Liu, X & Booth, PJ (2014), ‘Relative domain folding and stability of a membrane transport protein’. J Mol Biol, 426: 1812-1825
• Fletcher, J.M., Harniman, R.L., Barnes, F.R., Boyle, A.L., Collins, A., Mantell, J., Sharp, T.H., Antognozzi, M., Booth, P.J., Linden, N., Miles, M.J., Sessions, R.B., Verkade, P., Woolfson, D.N. (2013) Self-assembling cages from coiled-coil peptide modules Science 340:595-9
• Simms, J. & Booth, P.J. (2013) Membrane proteins by accident or design Curr Op. Chem. Biol. 17: 976-81
• Miller, D., Booth, P.J., Seddon, J.M., Templer, R.H., Law, R.V., Woscholski, R., Ces, O., Barter, L.M. (2013) Protocell design through modular compartmentalization. J R Soc Interface. 7 epub 20130496.
• Fletcher, JM, Boyle, AL, Bruning, M, Bartlett, GJ, Vincent, TL, Zaccai, NR, Armstrong, CT, Bromley, EHC, Booth, PJ, Brady, RL, Thomson, AR & Woolfson, DN 2012, ‘A basis set of de novo coiled-coil peptide oligomers for rational protein design and synthetic biology’. ACS Synth Biol, 1: 240-250
• Booth, P.J. (2012) A successful change of circumstance: a transition state for membrane protein folding Curr. Op. Struct. Biol 22:469-75.
• Curnow P., Senior L., Knight M.J., Thamatrakoln K., Hildebrand M., Booth P.J. (2012) Expression, purification, and reconstitution of a diatom silicon transporter. Biochemistry. 51:3776-85.
• Charalambous K., Booth, P.J., Woscholski, R., Seddon, J.M., Templer, R.H., Law, R.V., Barter, L.M., Ces, O. (2012) Engineering de-novo membrane mediated protein-protein communication networks J Am Chem Soc. 134: 5746-9.