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Journal article
Redox-Inactive Peptide Disrupting Trx1-Ask1 Interacion for Selective Activation of Stress Signaling
Biochemistry (Easton), v 57(5), pp 772-780
06 Feb 2018
PMID: 29261301
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Thioredoxin 1 (Trx1) and glutaredoxin 1 (Grx1) are two ubiquitous redox enzymes that are central for redox homeostasis but also are implicated in many other processes, including stress sensing, inflammation, and apoptosis. In addition to their enzymatic redox activity, a growing body of evidence shows that Trx1 and Grx1 play regulatory roles via protein-protein interactions with specific proteins, including Ask1. The currently available inhibitors of Trx1 and Grx1 are thiol-reactive electrophiles or disulfides that may suffer from low selectivity because of their thiol reactivity. In this report, we used a phage peptide library to identify a 7-mer peptide, 2GTP1, that binds to both Trx1 and Grx1. We further showed that a cell-permeable derivative of 2GTP1, TAT-2GTP1, disrupts the Trx1-Ask1 interaction, which induces Ask1 phosphorylation with subsequent activation of JNK, stabilization of p53, and reduced viability of cancer cells. Notably, as opposed to a disulfide-derived Trx1 inhibitor (PX-12), TAT-2GTP1 was selective for activating the Ask1 pathway without affecting other stress signaling pathways, such as endoplasmic reticulum stress and AMPK activation. Overall, 2GTP1 will serve as a useful probe for investigating protein interactions of Trx1.
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Details
- Title
- Redox-Inactive Peptide Disrupting Trx1-Ask1 Interacion for Selective Activation of Stress Signaling
- Creators
- Dilini N. Kekulandara - Wayne State UniversityShima Nagi - Wayne State UniversityHyosuk Seo - Wayne State UniversityChristine S. Chow - Wayne State UniversityYoung-Hoon Ahn - Wayne State University
- Publication Details
- Biochemistry (Easton), v 57(5), pp 772-780
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 9
- Grant note
- R01 HL131740-01A1 / National Institutes of Health Grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL131740 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Wayne State University start-up funds
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000424723300041
- Scopus ID
- 2-s2.0-85041458366
- Other Identifier
- 991020100215204721
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- Web of Science research areas
- Biochemistry & Molecular Biology