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Toxic Activation of...
Toxic Activation of an AAA plus Protease by the Antibacterial Drug Cyclomarin A
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Maurer, Michael (author)
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Linder, Daniela (author)
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Franke, Kamila B. (author)
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Jäger, Jasmin (author)
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Taylor, Gabrielle (author)
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Gloge, Felix (author)
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Gremer, Sebastian (author)
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Le Breton, Laura (author)
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Mayer, Matthias P. (author)
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Weber-Ban, Eilika (author)
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- Carroni, Marta (author)
- Stockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för biokemi och biofysik
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Bukau, Bernd (author)
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Mogk, Axel (author)
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English.
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In: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 26:8, s. 1169-1179
- Related links:
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https://doi.org/10.1...
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http://www.cell.com/...
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https://urn.kb.se/re...
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Abstract
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- ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an associated peptidase (e.g., ClpP). ATPase activity and substrate selection of AAA+ proteins are regulated by adapter proteins that bind to regulatory domains, such as the N-terminal domain (NTD). The antibacterial peptide Cyclomarin A (CymA) kills Mycobacterium tuberculosis cells by binding to the NTD of ClpC. How CymA affects ClpC function is unknown. Here, we reveal the mechanism of CymA-induced toxicity. We engineered a CymA-sensitized ClpC chimera and show that CymA activates ATPase and proteolytic activities. CymA mimics adapter binding and enables autonomous protein degradation by ClpC/ClpP with relaxed substrate selectivity. We reconstitute CymA toxicity in E. coli cells expressing engineered ClpC and ClpP, demonstrating that gain of uncontrolled proteolytic activity causes cell death. This validates drug-induced overriding of AAA+ protease activity control as effective antibacterial strategy.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Maurer, Michael
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Linder, Daniela
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Franke, Kamila B ...
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Jäger, Jasmin
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Taylor, Gabriell ...
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Gloge, Felix
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show more...
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Gremer, Sebastia ...
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Le Breton, Laura
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Mayer, Matthias ...
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Weber-Ban, Eilik ...
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Carroni, Marta
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Bukau, Bernd
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Mogk, Axel
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Cell Chemical Bi ...
- By the university
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Stockholm University