The architecture of thiol isomerases. Thiol isomerases consist of tandem domains containing a thioredoxin-fold. (A) The structure of the thioredoxin-fold.⁷  (B) PDI is formed from 4 tandem domains containing thioredoxin-like folds that assume a U-shape. The 2 catalytic domains (a and a′) contain the CGHC motifs that contain the catalytic cysteines (shown in red). The catalytic cysteines face one another and are responsible for oxidoreductive activities. The substrate binding domains (b and b′) form the bottom of the U-shape. The b′ domain contains a hydrophobic binding pocket that is primarily responsible for substrate binding. The b′ and a′ domains are connected by a flexible 19-amino-acid peptide termed the x-linker.