Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum

2017 ◽  
Vol 617 ◽  
pp. 106-119 ◽  
Author(s):  
Ana Iochabel Soares Moretti ◽  
Francisco Rafael Martins Laurindo
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Disulfide Isomerases ◽  
Disulfide Isomerases ◽  
Protein Disulfide

scholarly journals Inactivation of mammalian Ero1α is catalysed by specific protein disulfide-isomerases

2014 ◽  
Vol 461 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Colin Shepherd ◽  
Ojore B. V. Oka ◽  
Neil J. Bulleid
Keyword(s):  
Endoplasmic Reticulum ◽  
Catalytic Activity ◽  
Specific Protein ◽  
Disulfide Formation ◽  
Protein Disulfide Isomerases ◽  
Disulfide Isomerases ◽  
Protein Disulfide

The formation of disulfides in proteins that enter the endoplasmic reticulum is essential for their folding. We show in the present study that a key component of the machinery for disulfide formation is negatively regulated by the product of its catalytic activity.

scholarly journals Increasing Melanoma Cell Death Using Inhibitors of Protein Disulfide Isomerases to Abrogate Survival Responses to Endoplasmic Reticulum Stress

2008 ◽  
Vol 68 (13) ◽  
pp. 5363-5369 ◽  
Author(s):  
Penny E. Lovat ◽  
Marco Corazzari ◽  
Jane L. Armstrong ◽  
Shaun Martin ◽  
Vittoria Pagliarini ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Melanoma Cell ◽  
Protein Disulfide Isomerases ◽  
Disulfide Isomerases ◽  
Protein Disulfide

scholarly journals Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ryan Paxman ◽  
Lars Plate ◽  
Erik A Blackwood ◽  
Chris Glembotski ◽  
Evan T Powers ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Metabolic Activation ◽  
Covalent Modification ◽  
Unfolded Protein ◽  
Protein Disulfide Isomerases ◽  
Pathway Activation ◽  
Covalent Modifications ◽  
Disulfide Isomerases ◽  
Protein Response ◽  
Protein Disulfide

Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (147) was previously identified (<xref ref-type="bibr" rid="bib35">Plate et al., 2016</xref>) to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that 147-dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by 147 include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs 147-dependent induction of the ATF6-target gene, BiP, implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with 147. Thus, 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.

scholarly journals A druggable oxidative folding pathway in the endoplasmic reticulum of human malaria parasites

2020 ◽  
Author(s):  
David W. Cobb ◽  
Heather M. Kudyba ◽  
Alejandra Villegas ◽  
Michael R. Hoopmann ◽  
Rodrigo Baptista ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Drug Targets ◽  
Oxidative Folding ◽  
Small Molecule Inhibition ◽  
Protein Disulfide Isomerases ◽  
Redox Active ◽  
Parasite Survival ◽  
Disulfide Isomerases ◽  
Protein Disulfide ◽  
Global Health Problem

AbstractMalaria remains a major global health problem, and there exists a constant need to identify druggable weaknesses in P. falciparum biology. The endoplasmic reticulum (ER) has many essential roles in the asexual lifecycle and may offer new drug targets, but it remains critically understudied. We generated conditional mutants of the putative redox-active, ER chaperone PfJ2, and show that it is essential for parasite survival. Using a redox-active cysteine crosslinker, we identify its substrates to be other mediators of oxidative folding, PfPDI8 and PfPDI11, suggesting a redox-regulatory role for PfJ2. Knockdown of these protein disulfide isomerases in PfJ2 conditional mutants show that PfPDI11 is not essential, while PfPDI8 is essential for asexual growth and may work in a complex with PfJ2 and other ER chaperones. Finally, we show that these redox interactions in the parasite ER are sensitive to small molecule inhibition. Together these data build a model for how oxidative folding occurs in the P. falciparum ER and demonstrate its suitability for antimalarial drug development.

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