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 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.

De Novo Designed Peptidic Redox Potential Probe:  Linking Sensitized Emission to Disulfide Bond Formation

2004 ◽  
Vol 126 (42) ◽  
pp. 13616-13617 ◽  
Author(s):  
Kyung Lee ◽  
Valerie Dzubeck ◽  
Lauren Latshaw ◽  
Joel P. Schneider
Keyword(s):  
Redox Potential ◽  
Disulfide Bond ◽  
De Novo ◽  
Bond Formation ◽  
Disulfide Bond Formation

scholarly journals Redox-dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function

2015 ◽  
Vol 25 (3) ◽  
pp. 572-586 ◽  
Author(s):  
Mikko Laitaoja ◽  
Helena Tossavainen ◽  
Tero Pihlajamaa ◽  
Jarkko Valjakka ◽  
Keijo Viiri ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Bond Formation ◽  
Structure And Function ◽  
Disulfide Bond Formation ◽  
And Function

scholarly journals Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1994 ◽  
Author(s):  
Philip J. Robinson ◽  
Neil J. Bulleid
Keyword(s):  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Secretory Pathway ◽  
Bond Formation ◽  
Complex Problem ◽  
Structure Stability ◽  
Disulfide Bond Formation ◽  
Polypeptide Folding ◽  
Domains Of Life ◽  
And Function

Disulfide bonds are an abundant feature of proteins across all domains of life that are important for structure, stability, and function. In eukaryotic cells, a major site of disulfide bond formation is the endoplasmic reticulum (ER). How cysteines correctly pair during polypeptide folding to form the native disulfide bond pattern is a complex problem that is not fully understood. In this paper, the evidence for different folding mechanisms involved in ER-localised disulfide bond formation is reviewed with emphasis on events that occur during ER entry. Disulfide formation in nascent polypeptides is discussed with focus on (i) its mechanistic relationship with conformational folding, (ii) evidence for its occurrence at the co-translational stage during ER entry, and (iii) the role of protein disulfide isomerase (PDI) family members. This review highlights the complex array of cellular processes that influence disulfide bond formation and identifies key questions that need to be addressed to further understand this fundamental process.

scholarly journals DsbB Catalyzes Disulfide Bond Formation de Novo

2002 ◽  
Vol 277 (36) ◽  
pp. 32706-32713 ◽  
Author(s):  
James Regeimbal ◽  
James C. A. Bardwell
Keyword(s):  
Disulfide Bond ◽  
De Novo ◽  
Bond Formation ◽  
Disulfide Bond Formation ◽  
Formation De Novo

scholarly journals Functional studies of per os infectivity factor 3 of Helicoverpa armigera nucleopolyhedrovirus

2012 ◽  
Vol 93 (2) ◽  
pp. 374-382 ◽  
Author(s):  
Jingjiao Song ◽  
Manli Wang ◽  
Huachao Huang ◽  
Xin Luo ◽  
Fei Deng ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Helicoverpa Armigera ◽  
Disulfide Bonds ◽  
Bond Formation ◽  
Terminal Region ◽  
Disulfide Bond Formation ◽  
Functional Studies ◽  
Nuclear Ring ◽  
Helicoverpa Armígera ◽  
And Function

PIF3 is one of the six conserved per os infectivity factors (PIFs) of baculoviruses. In this study, PIF3 of Helicoverpa armigera nucleopolyhedrovirus (HearNPV) was analysed by infectivity bioassays using a series of recombinant viruses harbouring various PIF3 truncation/substitution mutants. The results demonstrated that the N-terminal region (L26–Y45) and C-terminal region (T160–Q199) are essential for HearNPV oral infectivity. In the C-terminal T160–Q199 region, there are three conserved cysteines (C162, C164 and C185). Our results showed that substitutions of C162 or C164, predicted to be involved in disulfide-bond formation, led to a severe decrease in HearNPV per os infectivity. Mutation of C185, predicted not to be involved in disulfide-bond formation, did not affect the per os infectivity. The data suggest that disulfide bonds are important for PIF3 conformation and function. Immunofluorescence assays showed that none of the mutations affected the subcellular localization of PIF3 to the nuclear ring zone region of infected cells. Western blot results showed that all mutants except C162G and C185G failed to incorporate PIF3 into occlusion-derived viruses, which resulted in impaired oral infectivity of the latter. The data provide insights for future study of PIF3 function.

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