Protein Disulfide Isomerase: A New Class of Drug Target

Protein Disulfide Isomerase (PDI) was originally discovered fifty years ago as the first protein folding catalyst and isolated from rat liver [1]. It was demonstrated early on that PDI acts as a dithiol–disulfide oxidoreductase capable of reducing, oxidizing and isomerizing disulfide bonds. Independently of its redox activity, PDI can also act as a vital cellular defense against the intracellular accumulation of misfolded proteins via its chaperone activity [2]. As of today, the PDI family comprises twenty members that vary in length and in the spatial arrangement of PDI-specific structural domains [3]. Indeed, most PDI family members share in common catalytic and noncatalytic thioredoxin-like domains. PDI is organized in four thioredoxin-like domains, a, a’, b and b’, in addition to a linker domain: x (Figure1). The and a’ domains contain catalytic CXXC motifs reacting with thiol groups in substrate proteins. Non catalytic domains b and b’ were shown to be involved in substrate recognition and recruitment [3]. Although PDIs are considered to be primarily ER resident proteins, several other cellular locations have been reported for these proteins including the cell surface, cytosol, mitochondria, and extracellular matrix [4]. Interestingly, several recent studies show the association of the extracellular PDIs with specific physiologic and physiopathologic processes [5]. The key roles played by these proteins in cell adhesion and thus inflammation, cardiovascular diseases, cancer and host-pathogen interaction suggest the potential use of PDI as novel therapeutic targets, which will be discussed in this review.