Disulphide bonds and metabolic disorders
The ability of secreted proteins to form a correct 3D structure depends on the formation of disulphide bonds between cysteine residues. Oxidative protein folding is a process that is responsible for the formation of these disulphide bonds. The driving force of the process is a redox reaction, in which electrons are passed between several proteins to a terminal electron acceptor. This process is catalysed by an enzymatic apparatus located in the lumen of the endoplasmic reticulum, an intracellular organelle that handles transport and secretion of newly synthesised proteins. The EU-funded 'Oxidative protein folding and pathogenesis of metabolic disorders' (ER AND METABOLISM) project is investigating the impact of genetic modifications of the enzymes involved in Oxidative protein folding in mouse models and in the cells derived from these mice. Genetically modified mice with deficiency in the enzymes mediating disulphide bond formation were produced through the techniques of germ line gene manipulation. Mutant mice with deficiencies in dithiol oxidase ERO1a, dithiol oxidase ERO1b and ER-localised peroxiredoxin (PRDX4) were produced and are now available to the research community. Combined loss–of–function mutations in genes encoding the ER thiol oxidases ERO1a, ERO1b and PRDX4 were compatible with the survival of mice. This indicates that the process of disulphide bond formation is highly redundant. These mutations compromised the extracellular matrix in mice and interfered with the intracellular maturation of pro-collagen. Ascorbic acid content was lower in mutant mice, and ascorbic acid supplementation improved pro-collagen maturation. This study indicates that compromised Oxidative protein folding results in the depletion of ascorbic acid, impaired pro-collagen maturation and a non-canonical form of scurvy. Research thus offers insight into the functional significance of Oxidative protein folding in live animals.
