scholarly journals Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2138
Author(s):  
Chaitanya Patel ◽  
Haddas Saad ◽  
Marina Shenkman ◽  
Gerardo Z. Lederkremer
Keyword(s):  
Disulfide Bond ◽  
Bond Formation ◽  
Large Family ◽  
Secretory Proteins ◽  
Specific Cell ◽  
Disulfide Bond Formation ◽  
Native Structure ◽  
Sugar Chain ◽  
Open Questions ◽  
Glycoprotein Glycosylation

N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.

A Secreted Disulfide Catalyst Controls Extracellular Matrix Composition and Function

Science ◽  
2013 ◽  
Vol 341 (6141) ◽  
pp. 74-76 ◽  
Author(s):  
Tal Ilani ◽  
Assaf Alon ◽  
Iris Grossman ◽  
Ben Horowitz ◽  
Elena Kartvelishvily ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Disulfide Bond ◽  
De Novo ◽  
Bond Formation ◽  
Supporting Cell ◽  
Matrix Composition ◽  
Secretory Proteins ◽  
Disulfide Bond Formation ◽  
Enzyme Families ◽  
And Function

Disulfide bond formation in secretory proteins occurs primarily in the endoplasmic reticulum (ER), where multiple enzyme families catalyze cysteine cross-linking. Quiescin sulfhydryl oxidase 1 (QSOX1) is an atypical disulfide catalyst, localized to the Golgi apparatus or secreted from cells. We examined the physiological function for extracellular catalysis of de novo disulfide bond formation by QSOX1. QSOX1 activity was required for incorporation of laminin into the extracellular matrix (ECM) synthesized by fibroblasts, and ECM produced without QSOX1 was defective in supporting cell-matrix adhesion. We developed an inhibitory monoclonal antibody against QSOX1 that could modulate ECM properties and undermine cell migration.

scholarly journals Two Pairs of Conserved Cysteines Are Required for the Oxidative Activity of Ero1p in Protein Disulfide Bond Formation in the Endoplasmic Reticulum

2000 ◽  
Vol 11 (9) ◽  
pp. 2833-2843 ◽  
Author(s):  
Alison R. Frand ◽  
Chris A. Kaiser
Keyword(s):  
Endoplasmic Reticulum ◽  
Disulfide Bond ◽  
Mutational Analysis ◽  
Bond Formation ◽  
Secretory Proteins ◽  
Disulfide Bond Formation ◽  
Major Pathway ◽  
Disulfide Exchange ◽  
Redox Active ◽  
Protein Disulfide

In the major pathway for protein disulfide-bond formation in the endoplasmic reticulum (ER), oxidizing equivalents flow from the conserved ER-membrane protein Ero1p to secretory proteins via protein disulfide isomerase (PDI). Herein, a mutational analysis of the yeast ERO1 gene identifies two pairs of conserved cysteines likely to form redox-active disulfide bonds in Ero1p. Cys100, Cys105, Cys352, and Cys355 of Ero1p are important for oxidative protein folding and for cell viability, whereas Cys90, Cys208, and Cys349 are dispensable for these functions. Substitution of Cys100 with alanine impedes the capture of Ero1p-Pdi1p mixed-disulfide complexes from yeast, and also blocks oxidation of Pdi1p in vivo. Cys352 and Cys355 are required to maintain the fully oxidized redox state of Ero1p, and also play an auxiliary role in thiol–disulfide exchange with Pdi1p. These results suggest a model for the function of Ero1p wherein Cys100 and Cys105 form a redox-active disulfide bond that engages directly in thiol–disulfide exchange with ER oxidoreductases. The Cys352–Cys355 disulfide could then serve to reoxidize the Cys100–Cys105 cysteine pair, possibly through an intramolecular thiol–disulfide exchange reaction.

scholarly journals Oxygen-independent disulfide bond formation in VEGF-A and CA9

2021 ◽  
pp. 100505
Author(s):  
Fiana Levitin ◽  
Sandy Che-Eun Serena Lee ◽  
Stephanie Hulme ◽  
Ryan A. Rumantir ◽  
Amy S. Wong ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Bond Formation ◽  
Disulfide Bond Formation

scholarly journals The Sex Differences in Uveal Melanoma: Potential Roles of EIF1AX, Immune Response and Redox Regulation

2021 ◽  
Vol 28 (4) ◽  
pp. 2801-2811
Author(s):  
Feng Liu-Smith ◽  
Chi-Yang Chiu ◽  
Daniel L. Johnson ◽  
Phillip Winston Miller ◽  
Evan S. Glazer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Sex Difference ◽  
Uveal Melanoma ◽  
Disulfide Bond ◽  
Bond Formation ◽  
Disulfide Bond Formation ◽  
Men And Women ◽  
Copy Numbers ◽  
Differential Gene

Background: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. Methods: This study used the SEER data (1974–2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. Results: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. Conclusion: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.

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