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Literature summary for 1.8.98.2 extracted from

  • Chawsheen, H.A.; Jiang, H.; Ying, Q.; Ding, N.; Thapa, P.; Wei, Q.
    The redox regulator sulfiredoxin forms a complex with thioredoxin domain-containing 5 protein in response to ER stress in lung cancer cells (2019), J. Biol. Chem., 294, 8991-9006 .
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
diagnostics the lung cancer patients with high Srx levels have significantly shorter survival and those with high TXNDC5 levels have longer survival. Cellular levels of Srx and TXNDC5 may be useful as biomarkers to predict the survival of individuals with lung cancer Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
transient recombinant expression of the FLAG-tagged enzyme in different cell types, including HEK293T, H226, and A549 cells, recombinant expression of FLAG-tagged Srx mutant C99A mutant in HEK-293T cells. The Srx-protein complex is pulled down by anti-FLAG immunoprecipitation (IP), and protein identities are determined by mass spectrometry. Among the handful of proteins identified, Prx4 is the most abundant protein, and TXNDC5 is the second most abundant protein that is specifically pulled down by anti-FLAG IP in all cell types. c-Myc-tagged TXNDC5 or its cysteine-specific mutants are expressed in HEK-293T-FLAG-Srx cells Homo sapiens

Protein Variants

Protein Variants Comment Organism
C99A site-directed mutagenesis, the mutation leads to a complete loss of both Srx enzymatic activity and binding to substrates such as Prxs Homo sapiens
additional information several lentiviral shRNAs targeting separate coding regions of Srx mRNA (shSrx) are used to knockdown the levels of endogenously expressed protein. Two shRNAs targeting the coding regions of TXNDC5 have the highest efficiency to inhibit the expression of endogenous protein. These shRNAs are introduced into A549 and H226 cells by viral infection. Enzyme knockdown in in stable A-549 or H-226 cells expressing shSrx1 or shSrx2. Knockdown of Srx leads to a rapid activation of the unfolded protein response (UPR) and sensitizes human lung cancer cells to ER stress-induced cell death Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoplasm mainly Homo sapiens 5737
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endoplasmic reticulum colocalization of Srx and TXNDC5 in endoplasmic reticulum of cultured cells Homo sapiens 5783
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Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
additional information Homo sapiens Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2 ?
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peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH Homo sapiens
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peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
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?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9BYN0
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Source Tissue

Source Tissue Comment Organism Textmining
A-549 cell derived from adenocarcinoma Homo sapiens
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HEK-293T cell
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Homo sapiens
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lung cancer cell Srx is highly expressed in primary specimen of lung cancer patients Homo sapiens
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NCI-H226 cell derived from squamous cell carcinoma Homo sapiens
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2 Homo sapiens ?
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additional information Srx transfers the gamma-phosphate of ATP to Cp sulfinic acid on hyperoxidized Prxs and produces sulfinic phosphoryl ester. Subsequent involvement of GSH and thioredoxin will ensure the reduction of sulfinic phosphoryl ester to sulfenic acid Homo sapiens ?
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peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
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Homo sapiens peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
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?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin
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Homo sapiens peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
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peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + GSH
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Homo sapiens peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + G-S-S-G
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?

Synonyms

Synonyms Comment Organism
Srx
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Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
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Homo sapiens

General Information

General Information Comment Organism
malfunction Srx knockdown sensitizes lung cancer cells to endoplasmic reticulum (ER) stress-induced cell death. Inhibition of Srx results in oxidative stress-induced mitochondrial damage and caspase activation, leading to the apoptosis of lung adenocarcinoma cells. Mutation of Cys99 to Ala (C99A) leads to a complete loss of both enzymatic activity and binding to substrates such as Prxs Homo sapiens
additional information Cys99 of Srx is critical for its catalytic activity Homo sapiens
physiological function Sulfiredoxin (Srx) reduces hyperoxidized 2-cysteine-containing peroxiredoxins (Prxs) and protects cells against oxidative stress. Cellular peroxidases, including Prxs, are antioxidant enzymes that contribute to the development of lung cancer. Srx is highly expressed in primary specimens of lung cancer patients and plays a pivotal role in lung tumorigenesis and cancer progression. Srx has an oncogenic function that promotes the invasion and metastasis of lung cancer cells. In response to ER stress but not to oxidative stress, Srx exhibits an increased association with the endoplasmic reticulum (ER)-resident protein thioredoxin domain-containing protein 5 (TXNDC5), facilitating the retention of Srx in the ER. The overall amounts of TXNDC5 associated with Srx are not affected by the exposure of cells to exogenous H2O2 as high as 1 mM, functional significance of Srx and TXNDC5 at different stages of lung cancer. Of note, TXNDC5 knockdown in lung cancer cells inhibits cell proliferation and represses anchorage-independent colony formation and migration, but increases cell invasion and activation of mitogen-activated protein kinases. Expression of TXNDC5 stimulates anchorage-independent colony formation but inhibits cell invasion. Knockdown of TXNDC5 enhances EGF-induced MAPK activation. TXNDC5 is highly expressed in patient-derived lung cancer specimen. Patients with high Srx levels have significantly shorter survival and those with high TXNDC5 levels have longer survival. The function of Srx appears to be necessary to maintain the redox balance in cancer cells Homo sapiens