ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate–partner associationsThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 881-889 ◽  
Author(s):  
P. Maattanen ◽  
G. Kozlov ◽  
K. Gehring ◽  
D.Y. Thomas
Keyword(s):  
Quality Control ◽  
Disulfide Bonds ◽  
Secretory Proteins ◽  
Er Quality Control ◽  
Multifunctional Protein ◽  
Health And Disease ◽  
Disulfide Isomerases ◽  
Protein Disulfide ◽  
Selection Of ◽  
Similar Domain

Secretory proteins become folded and acquire stabilizing disulfide bonds in the endoplasmic reticulum (ER). Correct disulfide bond formation is a key step in ER quality control (ERQC). Proteins with incorrect disulfide bonds are recognized by the quality control machinery and are retrotranslocated into the cytosol where they are degraded by the proteasome. The mammalian ER contains 17 disulfide isomerases and at least one of them, ERp57, works in conjunction with the ER lectin-like chaperones calnexin and calreticulin. The targeting of ERp57 to calnexin–calreticulin is mediated by its noncatalytic b′ domain, and analogous domains in other disulfide isomerases likely determine their substrate and partner preferences. This review discusses some explanations for the multiplicity of disulfide isomerases and highlights structural differences in the b′ domains of PDI and ERp57 as an example of how noncatalytic domains define specialized roles in oxidative folding.

scholarly journals Proteasome and thiol involvement in quality control of glycosylphosphatidylinositol anchor addition

1998 ◽  
Vol 332 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Barry WILBOURN ◽  
Darren N. NESBETH ◽  
Linda J. WAINWRIGHT ◽  
Mark C. FIELD
Keyword(s):  
Quality Control ◽  
Cysteine Residue ◽  
Retention Mechanism ◽  
Secretory Proteins ◽  
Aggregate Formation ◽  
Er Quality Control ◽  
Additional Information ◽  
Intracellular Degradation ◽  
Processing Signal ◽  
Ubiquitination System

Improperly processed secretory proteins are degraded by a hydrolytic system that is associated with the endoplasmic reticulum (ER) and appears to involve re-export of lumenal proteins into the cytoplasm for ultimate degradation by the proteasome. The chimaeric protein hGHDAF28, which contains a crippled glycosylphosphatidylinositol (GPI) C-terminal signal peptide, is degraded by a pathway highly similar to that for other ER-retained proteins and is characterized by formation of disulphide-linked aggregates, failure to reach the Golgi complex and intracellular degradation with a half life of ∼ 2 h. Here we show that N-acetyl-leucinal-leucinal-norleucinal, MG-132 and lactacystin, all inhibitors of the proteasome, protect hGHDAF28; hGHDAF28 is still proteolytically cleaved in the presence of lactacystin or MG-132, by the removal of ∼ 2 kDa, but the truncated fragment is not processed further. We demonstrate that the ubiquitination system accelerates ER-degradation of hGHDAF28, but is not essential to the process. Overall, these findings indicate that GPI quality control is mediated by the cytoplasmic proteasome. We also show that the presence of a cysteine residue in the GPI signal of hGHDAF28 is required for retention and degradation, as mutation of this residue to serine results in secretion of the fusion protein, implicating thiol-mediated retention as a mechanism for quality control of some GPI signals. Removal of the cysteine also prevents inclusion of hGHDAF28 in disulphide-linked aggregates, indicating that aggregate formation is an additional retention mechanism for this class of protein. Therefore our data suggest that an unpaired terminal cysteine is the retention motif of the hGHDAF28 GPI-processing signal and that additional information may be required for efficient engagement of ER quality control systems by the majority of GPI signals which lack cysteine residues.

scholarly journals Rapid expansion of the protein disulfide isomerase gene family facilitates the folding of venom peptides

2016 ◽  
Vol 113 (12) ◽  
pp. 3227-3232 ◽  
Author(s):  
Helena Safavi-Hemami ◽  
Qing Li ◽  
Ronneshia L. Jackson ◽  
Albert S. Song ◽  
Wouter Boomsma ◽  
...  
Keyword(s):  
Gene Family ◽  
Disulfide Bonds ◽  
Rapid Evolution ◽  
Rapid Expansion ◽  
Marine Snails ◽  
Venom Glands ◽  
Single Genus ◽  
Peptide Toxins ◽  
Disulfide Isomerases ◽  
Protein Disulfide

Formation of correct disulfide bonds in the endoplasmic reticulum is a crucial step for folding proteins destined for secretion. Protein disulfide isomerases (PDIs) play a central role in this process. We report a previously unidentified, hypervariable family of PDIs that represents the most diverse gene family of oxidoreductases described in a single genus to date. These enzymes are highly expressed specifically in the venom glands of predatory cone snails, animals that synthesize a remarkably diverse set of cysteine-rich peptide toxins (conotoxins). Enzymes in this PDI family, termed conotoxin-specific PDIs, significantly and differentially accelerate the kinetics of disulfide-bond formation of several conotoxins. Our results are consistent with a unique biological scenario associated with protein folding: The diversification of a family of foldases can be correlated with the rapid evolution of an unprecedented diversity of disulfide-rich structural domains expressed by venomous marine snails in the superfamily Conoidea.

scholarly journals Distribution of protein disulfide isomerase in rat epiphyseal chondrocytes.

1989 ◽  
Vol 37 (12) ◽  
pp. 1835-1844 ◽  
Author(s):  
S Akagi ◽  
A Yamamoto ◽  
T Yoshimori ◽  
R Masaki ◽  
R Ogawa ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein A ◽  
Secretory Proteins ◽  
Disulfide Isomerase ◽  
Gold Particles ◽  
Golgi Compartment ◽  
Preferential Binding ◽  
Protein Disulfide

We investigated the intracellular distribution of protein disulfide isomerase (PDI) in rat epiphyseal chondrocytes by immunocytochemistry, using a post-embedding protein A-gold technique. Gold particles were localized primarily in the cisternal space of the rough endoplasmic reticulum (ER) and nuclear envelopes. The ER cisternae of the chondrocytes in all the differentiating epiphyseal zones--resting, proliferative, pre-hypertrophic, and hypertrophic--were equally and highly labeled. The labeling density of the cisternal space of the dilated ER, probably reflecting marked accumulation of secretory proteins such as procollagen, was always higher than that of the non-dilated ER. In the dilated cisternal space, gold particles were freely and evenly distributed, without preferential binding to the luminal surface of the ER membranes. We suggest that PDI catalyzes the formation of disulfide bonds of various secretory proteins, perhaps type II procollagen, in the cisternal space of the ER in epiphyseal chondrocytes. The exclusive localization of gold particles in the cisternal space of the ER and nuclear envelopes and the lack of gold particles in the Golgi apparatus, including cis-Golgi cisternae, indicate that PDI is an ER-soluble protein in the chondrocytes and is presumably sorted out in some pre-Golgi compartment and not transported to the Golgi apparatus.

scholarly journals Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress

2019 ◽  
Author(s):  
Aeid Igbaria ◽  
Philip I. Merksamer ◽  
Ala Trusina ◽  
Firehiwot Tilahun ◽  
Jefferey R. Johnson ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Control Process ◽  
Secretory Proteins ◽  
Er Quality Control ◽  
Quality Control Process

ABSTRACTDiverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such “ER stress”, we employed an ER-targeted, redox-responsive, green fluorescent protein—eroGFP—that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress agents cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to “reflux” back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in S. cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and co-chaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER-protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.SIGNIFICANCEApproximately one third of eukaryotic proteins are synthesized on ribosomes attached to the endoplasmic reticulum (ER) membrane. Many of these polypeptides co- or post-translationally translocate into the ER, wherein they fold and mature. An ER quality-control system proofreads these proteins by facilitating their folding and modification, while eliminating misfolded proteins through ER-associated degradation (ERAD). Yet, the fate of many secretory proteins during ER stress is not completely understood. Here, we uncovered an ER-stress induced “protein reflux” system that delivers intact, folded ER luminal proteins back to the cytosol without degrading them. We found that ER protein reflux works in parallel to ERAD and requires distinct ER-resident and cytosolic chaperones and co-chaperones.

scholarly journals Analysis of the Isomerase and Chaperone-Like Activities of an Amebic PDI (EhPDI)

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rosa E. Mares ◽  
Alexis Z. Minchaca ◽  
Salvador Villagrana ◽  
Samuel G. Meléndez-López ◽  
Marco A. Ramos
Keyword(s):  
Protein Folding ◽  
Disulfide Bonds ◽  
Molecular Mechanisms ◽  
Thermal Inactivation ◽  
Initial Step ◽  
E Coli ◽  
Isomerase Activity ◽  
Disulfide Isomerases ◽  
Protein Disulfide

Protein disulfide isomerases (PDI) are eukaryotic oxidoreductases that catalyze the formation and rearrangement of disulfide bonds during folding of substrate proteins. Structurally, PDI enzymes share as a common feature the presence of at least one active thioredoxin-like domain. PDI enzymes are also involved in holding, refolding, and degradation of unfolded or misfolded proteins during stressful conditions. TheEhPDI enzyme (a 38 kDa polypeptide with two active thioredoxin-like domains) has been used as a model to gain insights into protein folding and disulfide bond formation inE. histolytica. Here, we performed a functional complementation assay, using a ΔdsbC mutant ofE. coli, to test whetherEhPDI exhibits isomerase activityin vivo. Our preliminary results showed thatEhPDI exhibits isomerase activity; however, further mutagenic analysis revealed significant differences in the functional role of each thioredoxin-like domain. Additional studies confirmed thatEhPDI protects heat-labile enzymes against thermal inactivation, extending our knowledge about its chaperone-like activity. The characterization ofEhPDI, as an oxidative folding catalyst with chaperone-like function, represents the initial step to dissect the molecular mechanisms involved in protein folding inE. histolytica.

scholarly journals Export of a Cysteine-Free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase

1999 ◽  
Vol 147 (7) ◽  
pp. 1443-1456 ◽  
Author(s):  
Pauline Gillece ◽  
José Manuel Luz ◽  
William J. Lennarz ◽  
Francisco Javier de la Cruz ◽  
Karin Römisch
Keyword(s):  
Quality Control ◽  
Protein Disulfide Isomerase ◽  
Secretory Protein ◽  
Secretory Proteins ◽  
Disulfide Isomerase ◽  
Thiol Content ◽  
Mutant Forms ◽  
Protein Disulfide ◽  
Chemical Cross Linking ◽  
Er Membrane

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the molecule to investigate its role in the recognition of misfolded secretory proteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.

scholarly journals A unique adhesive motif of protein disulfide isomerase P5 supports its function via dimerization

2020 ◽  
Author(s):  
Masaki Okumura ◽  
Shingo Kanemura ◽  
Motonori Matsusaki ◽  
Misaki Kinoshita ◽  
Tomohide Saio ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Leucine Zipper ◽  
Structural Instability ◽  
Er Quality Control ◽  
Er Stress Response ◽  
Chaperone Function ◽  
Intermolecular Disulfide Bonds ◽  
Local Unfolding ◽  
Protein Disulfide

SUMMARYP5, also known as PDIA6, is a PDI-family member that plays an important role in the ER quality control. Herein, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. This motif is apparently similar to, but radically different from conventional leucine-zipper motifs, in that the former includes a periodic repeat of leucine or valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α-helices, unlike the latter of which the leucine residues appear every two helical turns on ∼30-residue parallel α-helices at dimer interfaces. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as an aberrant protein that induces the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via reduction of intermolecular disulfide bonds and its Ca2+-dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and physiological function of P5.

scholarly journals Endoplasmic Reticulum Chaperones Are Involved in the Morphogenesis of Rotavirus Infectious Particles

2008 ◽  
Vol 82 (11) ◽  
pp. 5368-5380 ◽  
Author(s):  
Liliana Maruri-Avidal ◽  
Susana López ◽  
Carlos F. Arias
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Infectious Virus ◽  
The Other ◽  
Disulfide Isomerase ◽  
Virus Particles ◽  
Final Assembly ◽  
Protein Disulfide

ABSTRACT The final assembly of rotavirus particles takes place in the endoplasmic reticulum (ER). In this work, we evaluated by RNA interference the relevance to rotavirus assembly and infectivity of grp78, protein disulfide isomerase (PDI), grp94, calnexin, calreticulin, and ERp57, members of the two ER folding systems described herein. Silencing the expression of grp94 and Erp57 had no effect on rotavirus infectivity, while knocking down the expression of any of the other four chaperons caused a reduction in the yield of infectious virus of about 50%. In grp78-silenced cells, the maturation of the oligosaccharide chains of NSP4 was retarded. In cells with reduced levels of calnexin, the oxidative folding of VP7 was impaired and the trimming of NSP4 was accelerated, and in calreticulin-silenced cells, the formation of disulfide bonds of VP7 was also accelerated. The knockdown of PDI impaired the formation and/or rearrangement of the VP7 disulfide bonds. All these conditions also affected the correct assembly of virus particles, since compared with virions from control cells, they showed an altered susceptibility to EGTA and heat treatments, a decreased specific infectivity, and a diminished reactivity to VP7 with monoclonal antibody M60, which recognizes only this protein when its disulfide bonds have been correctly formed. In the case of grp78-silenced cells, the virus produced bound less efficiently to MA104 cells than virus obtained from control cells. All these results suggest that these chaperones are involved in the quality control of rotavirus morphogenesis. The complexity of the steps of rotavirus assembly that occur in the ER provide a useful model for studying the organization and operation of the complex network of chaperones involved in maintaining the quality control of this organelle.

scholarly journals Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase

Cell Reports ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 27-37.e4 ◽  
Author(s):  
Lars Schlotawa ◽  
Michaela Wachs ◽  
Olaf Bernhard ◽  
Franz J. Mayer ◽  
Thomas Dierks ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Disulfide Isomerase ◽  
Er Quality Control ◽  
Disulfide Isomerase ◽  
Protein Disulfide
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