Peptide Binding by Catalytic Domains of the Protein Disulfide Isomerase-Related Protein ERp46

The protein disulfide isomerase (PDI) family member ERp46/endoPDI/thioredoxin domain-containing protein 5 is preferentially expressed in a limited number of tissues, where it may function as a survival factor for nitrosative stress in vivo. It is involved in insulin production as well as in adiponectin signaling and interacts specifically with the redox-regulatory endoplasmic reticulum proteins endoplasmic oxidoreductin 1α (Ero1α) and peroxiredoxin-4. Here, we show that ERp46, although lacking a PDI-like redox-inactive b′-thioredoxin domain with its hydrophobic substrate binding site, is able to bind to a large pool of peptides containing aromatic and basic residues via all three of its catalytic domains (a0, a and a′), though the a0 domain may contain the primary binding site. ERp46, which shows relatively higher activity as a disulfide-reductase than as an oxidase/isomerase in vitro compared to PDI and ERp57, possesses chaperone activity in vivo, a property also shared by the C-terminal a′ domain. A crystal structure of the a′ domain is also presented, offering a view of possible substrate binding sites within catalytic domains of PDI proteins.

Graphical AbstractFigure optionsDownload high-quality image (114 K)Download as PowerPoint slideHighlights
► Do redox-active PDI-like domains have redox-independent peptide binding activity?
► We present a novel approach to study the weak PDI protein: peptide interactions.
► ERp46 lacks a PDI-like redox-inactive domain but binds a large pool of peptides.
► The major binding site is in the a0 domain, but all three ERp46 domains bind peptides.
► Redox-active domains of a PDI protein show redox-independent peptide binding.