National Doctoral Programme in
Informational and Structural Biology

Disulphide bonds are covalent linkages formed between two cysteine residues in proteins, whose primary function is to stabilize the folded structure of the protein. They are found in most outer membrane and secreted proteins, including receptors, peptide hormones, cytokines and antibodies. Their formation is complex and is usually the rate limiting step in the folding of such proteins.

While an extensive programme of work by many groups has provided a general picture of native disulphide bond formation in the endoplasmic reticulum (ER), the role played by individual proteins is still uncertain. The research in the group is focused on determining the function and mechanism of action of individual proteins in this biological system and on understanding the functional significance of cross-talk between interacting proteins.

Native disulphide bond formation in the ER can occur via multiple parallel pathways and this significantly complicates the interpretation of in vivo data. What is clear is that the rate-limiting step for native disulphide bond formation in proteins that contain multiple disulphides is late-stage isomerisation reactions, where disulphide bond formation is linked to conformational changes in protein substrates with substantial regular secondary structure. These steps are thought to only be catalysed by proteins belonging to the protein disulphide isomerase (PDI) family and hence an understanding of the mechanisms of action of the PDI family is the primary focus of our current research.

In addition to their role in disulphide bond formation the PDI family are also involved in a range of other cellular functions including collagen biogenesis (via prolyl-4-hydroxylation), loading MHC with antigens and hypoxia.