Structural Insights into the Redox-Regulated Dynamic Conformations of Human Protein Disulfide Isomerase

Abstract

The redox-regulated open/closed conformational switch of hPDI endows the protein with versatile target-binding capacities for its enzymatic and chaperone functions.

Novel Roles of the Non-catalytic Elements of Yeast Protein-disulfide Isomerase in Its Interplay with Endoplasmic Reticulum Oxidoreductin 1

“…In the endoplasmic reticulum (ER) 3 lumen of eukaryotic cells, the pivotal enzymatic pathway for catalyzing faithful disulfide formation is composed of sulfhydryl oxidase ER oxidoreductin 1 (Ero1) and protein-disulfide isomerase (PDI), which is conserved from yeast (Ero1p-Pdi1p) to human (Ero1␣/␤-PDI) (1)(2)(3). Both yeast Pdi1p and human PDI consist of four thioredoxin (Trx)-like domains, in the order of a, b, bЈ, and aЈ, with an x-linker between domains bЈ and aЈ and a carboxyl-terminal tail c (4,5). The a and aЈ domains each contain a -Cys-Gly-His-Cysactive site responsible for thiol-disulfide interchange reactions and the bЈ domain possesses a hydrophobic pocket, which serves as the principal client-binding site (6 -8).…”

The redox switch that regulates molecular chaperones

“…In human PDI (hPDI) and yeast, there are four thioredoxin-like domains (a, a', b, and b'). Structurally, these are arranged in a 'U-shaped' assembly where the a/a' domains face each other, each containing a solvent-exposed catalytic redox-active -CGHC-motif (49), where the thiols can cycle between an intramolecular disulphide bond or a reduced state and are responsible for the thiol-disulphide isomerase activity of PDI. As an oxidoreductase, oxidised PDI transfers its electrons to reduced substrates, forming a mixed disulphide.…”

“…Although the concept of PDI as a redox-regulated chaperone was challenged at the time, largely because this redox-regulated chaperone function could not be repeated for other proteins (64), the elucidation of the 3D structure of PDI in its reduced and oxidised form now provides strong evidence in support of this mechanism (49,63,62). Initial studies by Tsai et al in 2001 showed that PDI adopted a more compact structure in the reduced form.…”

“…Initial studies by Tsai et al in 2001 showed that PDI adopted a more compact structure in the reduced form. In the reduced and oxidised forms, a conformational shift induced by oxidation of the -CGHC-motif of the a' subunit created a change in the rotation of the C-terminal of the x-linker, exposing a greater surface area of the hydrophobic area of the b' domain ( Figure 5) (49). When oxidised, the distance between the two active -CGHC-regions increases by 12.7 Å.…”

Medidas das atividades da Dissulfeto Isomerase Proteica: uma análise crítica

“…PDI is formed by four thioredoxin-like structural domains, where only two contain the CGHC catalytic motif capable of catalyzing sulfydryl oxidation and isomerization of disulfide bonds Appenzeller-Herzog and Ellgaard, 2008). PDI also prevents protein aggregation, a chaperone effect that is not directly related to its redox thiols, and strictly related to the hydrophobic pocket found in one non-redox domain (Wang et al, 2013). PDI binds in vitro to a variety of molecules, from small peptides to proteins, but in vivo few client proteins were shown so far ).…”