The folding catalyst protein disulfide isomerase is constructed of active and inactive thioredoxin modules

Abstract

Our determination of the global fold of the b domain of PDI by NMR reveals that, like the a domain, the b domain contains the thioredoxin motif, even though the b domain has no significant amino-acid sequence similarities to any members of the thioredoxin family. This observation, together with indications that the b' domain adopts a similar fold, suggests that PDI consists of active and inactive thioredoxin modules. These modules may have been adapted during evolution to provide PDI with its complete spectrum of enzymatic activities.

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

“…The groups of Creighton [9] and So$ ling [10] have recently shown that PDI is composed of four thioredoxin domains, and not two as was previously believed. The model of the domain structure of PDI, as shown in Figure 2, is based on our previous work [10] and has been adjusted for and combined with the structural data supplied for the b domain [9] and extended to accommodate all domains and all members of the family (see Figure 3).…”

“…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.…”

“…This large family accommodates thioredoxin-like, glutaredoxin-like and PDI-like proteins, as well as members of the bacterial Dsb family [14,26,42,43], all of which contain one or more copies of the highly conserved thioredoxin fold, i.e. a β-α-β-α-β-α-β-β-α structure (as shown in Figures 1 and 2) encompassing a reactive -Cys-Xaa-Xaa-Cys-tetrapeptide [9,34,[44][45][46].…”

“…The model of the domain structure of PDI, as shown in Figure 2, is based on our previous work [10] and has been adjusted for and combined with the structural data supplied for the b domain [9] and extended to accommodate all domains and all members of the family (see Figure 3). This model differs significantly from the earlier model suggested by Freedman's group [8].…”

“…The positions of secondary-structure elements, as determined by NMR [9], are shown above the domain structure (α-helices and β-strand elements are represented by red boxes and black arrows respectively). Horizontal bars below the domain structure indicate possible peptide-binding sites.…”