Booth lab Membrane Protein Folding laboratory

Integral membrane proteins are proteins that are permanently attached to a cell’s membrane, and account for about 30% of all cell proteins. They provide the means for vital communication across the membrane in the form of transporting molecules across the membrane, as well as receiving, translating and transmitting signals. 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 is very likely to have pathological consequences, leading 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 our 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 particularly interested in the natural biosynthetic co-translational process, whereby new membrane proteins insert and fold in a membrane whilst being synthesised. Our co-translational studies also allow us to identify when misfolding can occur during protein synthesis. Several proteins, including a variety of transport proteins and membrane proteases, are studied in bacterial, yeast and cell-free expression systems. We use an interdisciplinary approach that includes using spectroscopy to measure folding kinetics, calorimetry to probe the amount of energy involved, Cryogenic electron microscopy to probe the structure of trapped intermediates, computer simulations and modelling, genetic or chemical modification methods to investigate folding intermediates and manipulation of the lipid environment to control the folding.