Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin

Abstract

The formation of disulphide bonds is essential to the structure and function of proteins. These bonds rapidly form either cotranslationally or immediately post-translationally in the lumen of the endoplasmic reticulum. Native disulphide pairing for such proteins has been achieved in vitro; however, the rates of reassembly are slow and the conditions non-physiological. To account for these observations, Anfinsen et al. proposed that a 'disulphide interchange protein' was the in vivo catalyst of disulphide bond rearrangement. Other groups discovered an activity with similar characteristics that catalysed the reductive cleavage of insulin and may be associated with insulin degradation, although this result has been disputed. The enzyme involved, protein disulphide isomerase (PDI; EC 5.3.4.1), may be the in vivo catalyst of disulphide bond formation. Here we describe the sequence of cloned rat liver PDI complementary DNA which predicts a protein with two distinct regions homologous with Escherichia coli thioredoxin, a known cofactor in oxidation-reduction reactions. Each of these regions contains the presumed active site sequence Trp-Cys-Gly-His-Cys-Lys, suggesting that PDI, similar in action to thioredoxin, catalyses disulphide bond interchange via an internal disulphide-sulphydryl interchange. The cDNA predicts a signal peptide consistent with the view that PDI is a luminal endoplasmic reticulum protein. PDI messenger RNA, although ubiquitous, is more highly concentrated in secretory cells.

Human IgGFc Binding Protein (FcγBP) in Colonic Epithelial Cells Exhibits Mucin-like Structure

“…3, Fc␥BP, vWF, and MUC2 all have the conserved amino acid motif CGLCGN. These sequences are also characteristic of thioredoxin (28) and protein disulfide isomerase (29). Another feature of this protein is that it is high in cysteine content.…”

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

“…80 PDI has two domains that are homologous to the small, redox-active protein TRX. 81 The two thiol/disulfide centers of these TRX-like domains function as independent active sites. 82 Accumulation of immature and denatured proteins results in ER dysfunction in brains of AD, PD, ALS, prion disease, cerebral ischemia, and possibly other neurodegenerative disorders, but upregulation of PDI represents an adaptive response promoting protein refolding and may offer neuronal cell protection.…”

The protein disulphide-isomerase family: unravelling a string of folds

“…Its structure encompasses two double-cysteine, redox-active sites, each within domains with high sequence similarity to thioredoxin [7,8], separated by a further two thioredoxin-related domains (hereafter referred to as thioredoxin fold domains) lacking reactive cysteines [9,10]. It is a highly abundant ER luminal including peptide binding, cell adhesion and perhaps chaperone activities.…”