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.
We have several close collaborations with research groups in this country and abroad.
Kalypso Charalambous, Natalie DiBartolo, Heather Findlay, Nicola Harris, Xia Liu, Eliza Ploskon-Arthur, Laura Senior, John Simms, Sara Wagner.
Curnow P, Di Bartolo ND, Moreton KM, Ajoje OO, Saggese NP, Booth PJ. (2011) A stable folding core in the folding transition state of an alpha-helical integral membrane protein. PNAS USA. 108:14133-14138.
Di Bartolo ND, Hvorup RN, Locher KP, Booth PJ. (2011) In Vitro Folding and Assembly of the Escherichia coli ATP-binding Cassette Transporter, BtuCD. Journal of Biological Chemistry. 286: 18807-18815.
Findlay HE, Rutherford NG, Henderson PJF, Booth PJ. (2010) The unfolding free energy of a two-domain transmembrane sugar transport protein. Proceedings of the National Academy of Sciences USA. 107: 18451-18456.
Barrera NP, Di Bartolo N, Booth PJ, Robinson CV. (2008) Micelles Protect Membrane Complexes from Solution to Vacuum. Science. 321: 243-24 .