scholarly journals Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides

2015 ◽  
Vol 26 (19) ◽  
pp. 3390-3400 ◽  
Author(s):  
Giorgia Brambilla Pisoni ◽  
Lloyd W. Ruddock ◽  
Neil Bulleid ◽  
Maurizio Molinari
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Client Protein ◽  
Redox Catalyst ◽  
The Family ◽  
Associated Proteins ◽  
Intermolecular Disulfide Bonds ◽  
Protein Disulfide ◽  
Rate Limiting ◽  
Er Membrane

The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. The lumen of the mammalian ER contains >20 members of the protein disulfide isomerase (PDI) superfamily, which ensure formation of the correct set of intramolecular and intermolecular disulfide bonds as crucial, rate-limiting reactions of the protein folding process. Components of the PDI superfamily may also facilitate dislocation of misfolded polypeptides across the ER membrane for ER-associated degradation (ERAD). The reasons for the high redundancy of PDI family members and the substrate features required for preferential engagement of one or the other are poorly understood. Here we show that TMX1, one of the few transmembrane members of the family, forms functional complexes with the ER lectin calnexin and preferentially intervenes during maturation of cysteine-containing, membrane-associated proteins while ignoring the same cysteine-containing ectodomains if not anchored at the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst in living cells.

scholarly journals Structural and mechanistic aspects of S-S bonds in the thioredoxin-like family of proteins

2019 ◽  
Vol 400 (5) ◽  
pp. 575-587 ◽  
Author(s):  
Sérgio F. Sousa ◽  
Rui P.P. Neves ◽  
Sodiq O. Waheed ◽  
Pedro A. Fernandes ◽  
Maria João Ramos
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Critical Role ◽  
Exchange Reactions ◽  
Disulfide Exchange ◽  
Active Site Cysteine ◽  
The Family ◽  
Protein Disulfide ◽  
Extracellular Environment ◽  
Insight Into

Abstract Disulfide bonds play a critical role in a variety of structural and mechanistic processes associated with proteins inside the cells and in the extracellular environment. The thioredoxin family of proteins like thioredoxin (Trx), glutaredoxin (Grx) and protein disulfide isomerase, are involved in the formation, transfer or isomerization of disulfide bonds through a characteristic thiol-disulfide exchange reaction. Here, we review the structural and mechanistic determinants behind the thiol-disulfide exchange reactions for the different enzyme types within this family, rationalizing the known experimental data in light of the results from computational studies. The analysis sheds new atomic-level insight into the structural and mechanistic variations that characterize the different enzymes in the family, helping to explain the associated functional diversity. Furthermore, we review here a pattern of stabilization/destabilization of the conserved active-site cysteine residues presented beforehand, which is fully consistent with the observed roles played by the thioredoxin family of enzymes.

scholarly journals Protein disulfide isomerase activity is released by activated platelets

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2226-2228 ◽  
Author(s):  
K Chen ◽  
Y Lin ◽  
TC Detwiler
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Ph Dependence ◽  
Gel Filtration ◽  
Disulfide Isomerase ◽  
Isomerase Activity ◽  
Activated Platelets ◽  
Protein Disulfide ◽  
Supernatant Solution ◽  
Disulfide Isomerase Activity

Abstract The release of protein disulfide isomerase by activated platelets was hypothesized on the basis of reported intermolecular and intramolecular thiol-disulfide exchange and disulfide reduction involving released thrombospondin in the supernatant solution of activated platelets (Danishefsky, Alexander, Detwiler: Biochemistry, 23:4984, 1984; Speziale, Detwiler: J Biol Chem, 265:17859, 1990; Speziale, Detwiler: Arch Biochem Biophys 286:546, 1991). Protein disulfide isomerase activity, measured by catalysis of the renaturation of ribonuclease inactivated by randomization of disulfide bonds, was detected in the supernatant solution after platelet activation. The activity was inhibited by peptides known to inhibit protein disulfide isomerase; the peptides also inhibited formation of disulfide-linked thrombospondin- thrombin complexes. The reaction catalyzed by the supernatant solution showed a pH dependence distinct from that of the uncatalyzed reaction. The activity was excluded by a 50-Kd dialysis membrane, and it was eluted in the void volume of a gel-filtration column, indicating that it was associated with a macromolecule. The activity was not removed by centrifugation at 100,000 g for 150 minutes indicating that it was not associated with membrane microvesicles. Possible functions for the release of protein disulfide isomerase by activated platelets are discussed.

scholarly journals Localization of protein disulfide isomerase to the external surface of the platelet plasma membrane

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2168-2173 ◽  
Author(s):  
DW Essex ◽  
K Chen ◽  
M Swiatkowska
Keyword(s):  
Indirect Immunofluorescence ◽  
Blood Cells ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Immunofluorescence Microscopy ◽  
External Surface ◽  
Platelet Surface ◽  
Disulfide Isomerase ◽  
Indirect Immunofluorescence Microscopy ◽  
Protein Disulfide

Protein disulfide isomerase (PDI) is an enzyme that catalyzes the formation as well as the isomerization of disulfide bonds. In this study, antibodies against PDI were used to show PDI antigen on the platelet surface by indirect immunofluorescence microscopy and by flow cytometry. The platelets were not activated, as evidenced by the absence of staining by an antibody against P-selectin. Permeabilized platelets showed little cytosolic PDI by indirect immunofluorescence microscopy, suggesting that the majority of platelet PDI is localized to the platelet surface. PDI activity against “scrambled” RNase was shown with intact platelets. The activity was inhibited by inhibitors of PDI and by an antibody against PDI. Other blood cells showed little PDI. Platelet surface PDI may play a role in the various physiological and pathophysiologic processes in which platelets are involved.

scholarly journals The anterior gradient-2 interactome

2020 ◽  
Vol 318 (1) ◽  
pp. C40-C47 ◽  
Author(s):  
Frederic Delom ◽  
M. Aiman Mohtar ◽  
Ted Hupp ◽  
Delphine Fessart
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Physiological Role ◽  
Disulfide Isomerase ◽  
Cellular Effects ◽  
Binding Partners ◽  
Protein Disulfide ◽  
Biological Outcomes

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

scholarly journals Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

2019 ◽  
Vol 57 (4) ◽  
pp. 274-282 ◽  
Author(s):  
Shereen Georges Ghosh ◽  
Lu Wang ◽  
Martin W Breuss ◽  
Joshua D Green ◽  
Valentina Stanley ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Transmembrane Protein ◽  
Repeat Expansion ◽  
Global Developmental Delay ◽  
Disulfide Isomerase ◽  
Whole Exome ◽  
Brain Malformations ◽  
Repeat Expansions ◽  
Protein Disulfide

BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

scholarly journals Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1

2002 ◽  
Vol 159 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Billy Tsai ◽  
Tom A. Rapoport
Keyword(s):  
Toxic Effect ◽  
Cholera Toxin ◽  
Disulfide Bond ◽  
Protein Disulfide Isomerase ◽  
Reduced Form ◽  
Target Cells ◽  
Disulfide Isomerase ◽  
Toxin Complex ◽  
Protein Disulfide ◽  
Er Membrane

The toxic effect of cholera toxin (CT) on target cells is caused by its A1 chain. This polypeptide is released from the holotoxin and unfolded in the lumen of the ER by the action of protein disulfide isomerase (PDI), before being retrotranslocated into the cytosol. The polypeptide is initially unfolded by binding to the reduced form of PDI. We show that upon oxidation of the COOH-terminal disulfide bond in PDI by the enzyme Ero1, the A1 chain is released. Both yeast Ero1 and the mammalian Ero1α isoform are active in this reaction. Ero1 has a preference for the PDI–toxin complex. We further show that the complex is transferred to a protein at the lumenal side of the ER membrane, where the unfolded toxin is released from PDI by the action of Ero1. Taken together, our results identify Ero1 as the enzyme mediating the release of unfolded CT from PDI and characterize an additional step in retrotranslocation of the toxin.

A role for the thiol isomerase protein ERP5 in platelet function

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1500-1507 ◽  
Author(s):  
Peter A. Jordan ◽  
Joanne M. Stevens ◽  
Gary P. Hubbard ◽  
Natasha E. Barrett ◽  
Tanya Sage ◽  
...  
Keyword(s):  
Cell Surface ◽  
Platelet Activation ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Human Platelet ◽  
Fibrinogen Binding ◽  
Endoplasmic Reticulum Protein ◽  
Inhibitory Antibodies ◽  
Activation Pathways ◽  
Protein Disulfide

Abstract Formation and rearrangement of disulfide bonds during the correct folding of nascent proteins is modulated by a family of enzymes known as thiol isomerases, which include protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERP5), and ERP57. Recent evidence supports an alternative role for this family of proteins on the surface of cells, where they are involved in receptor remodeling and recognition. In platelets, blocking PDI with inhibitory antibodies inhibits a number of platelet activation pathways, including aggregation, secretion, and fibrinogen binding. Analysis of human platelet membrane fractions identified the presence of the thiol isomerase protein ERP5. Further study showed that ERP5 is resident mainly on platelet intracellular membranes, although it is rapidly recruited to the cell surface in response to a range of platelet agonists. Blocking cell-surface ERP5 using inhibitory antibodies leads to a decrease in platelet aggregation in response to agonists, and a decrease in fibrinogen binding and P-selectin exposure. It is possible that this is based on the disruption of integrin function, as we observed that ERP5 becomes physically associated with the integrin β3 subunit during platelet stimulation. These results provide new insights into the involvement of thiol isomerases and regulation of platelet activation.

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