My Research Vision
Up to one third of the proteins produced by eukaryotic cells fold in the endoplasmic reticulum. Many of these proteins depend on disulphide bond formation, which is catalysed by a group of proteins called protein disulphide isomerases. My research interests lie in understanding this process at the molecular level. Obtaining detailed knowledge of the structure and function of these proteins will help us understand a fundamental and essential biological process and will provide insight into diseases that occur when protein folding goes wrong
In 2000 I obtained my Ph.D. at University of Copenhagen having worked with Professor Welinder on the catalytic mechanisms of plant peroxidises.
After completing my PhD, I joined Dr Downing’s group at Oxford University working on structure determination of a range of extracellular proteins. During this period I became increasingly interested in how secreted proteins fold and in particular how disulphide bonds are incorporated, making the folding process more complicated than for non-disulphide bonded proteins.
In order to pursue this line of research, I joined Professor Freedman’s group at University of Warwick in 2004 and began working on protein disulphide isomerases (PDIs), the enzymes that catalyse disulphide bond formation in eukaryotes. During this time, we determined the location of the substrate binding site in human PDI and characterised the mechanism of substrate binding and the inter-domain dynamics of this protein.
I joined Coventry University in 2013 to continue my research into the structure and function of mammalian PDIs.
- Wang, C., Chen, S., Wang, X., Wang, L., Wallis, A.K., Freedman, R.B., and Wang, C.C. (2010) 'Plasticity of human protein disulphide isomerase: Evidence for mobility around the x-linker region and its functional significance'. Journal of Biological Chemistry 285, 26788-26797.
- Binding b’ domain of human protein disulphide isomerase mediates homo-dimerization'. Protein science: a publication of the Protein Society 18, 2569-2577.
- Byre, L.J., Sidhu, A., Wallis, A.K., Ruddock, L.W., Freedman, R.B., Howard, M.J., and Williamson, R.A. (2009) 'Mapping of the ligand binding site on the b’ domain of human PDI; interaction with peptide ligands and the x-linker region'. Biochemical Journal 423, 209-217.
- Nguyen, V.D., Wallis, K., Howard, M.J., Haapalainen, A.M., Salo, K.E.H., Saaranen, M.J., Sidhu, A., Wierenga, R.K., Freedman, R.B., Ruddock, L.W., and Williamson, R.A. (2008) 'Alternative conformations of the x region of human protein disulphide-isomerase modulate exposure of the substrate-binding b’ domain'. Journal of Molecular Biology 383 (5), 1144-1155.
- Amin, N.T., Wallis, A.K., Wells, S.A., Rowe, M.L., Williamson, R.A., Howard, M.J., and Freedman, R.B. (2013) 'High-resolution NMR studies of structure and dynamics of human ERp27 indicate extensive interdomain flexibility'. Biochemical Journal 450, 321-332.
- Characterisation of P5 : P5 is a member of the protein disulphide isomerase (PDI) family. Very little is known about this protein and I am particularly interested in how it interacts with its substrates.
- Developing new assays for PDI: Various PDI assays are available for characterising the different properties of this multi-functional enzyme. However, many are labour intensive or involve poorly defined reactions, so I am developing new, more robust assays to measure PDI activity.
- Structure determination of PDIs : The number of structures of full-length or truncated or PDIs is steadily increasing, but the inter-domain dynamics is still poorly understood. Further structure determination is necessary to understand how PDI function.