The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease

Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review

Autoren

  • Janine Kirstein
  • Anja Hoffmann
  • Hauke Lilie
  • Ronny Schmidt
  • Rubsamen Waigmann Helga
  • Brötz Oesterhelt Heike
  • Axel Mogk
  • Kürşad Turgay

Externe Organisationen

  • Freie Universität Berlin (FU Berlin)
  • Ruprecht-Karls-Universität Heidelberg
  • Martin-Luther-Universität Halle-Wittenberg
  • AiCuris GmbH and Co. KG
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Seiten (von - bis)37-49
Seitenumfang13
FachzeitschriftEMBO molecular medicine
Jahrgang1
Ausgabenummer1
PublikationsstatusVeröffentlicht - 26 März 2009
Extern publiziertJa

Abstract

A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degradation. Here, we analyse the molecular mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hspi00 adenosine triphosphatases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.

ASJC Scopus Sachgebiete

Zitieren

The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease. / Kirstein, Janine; Hoffmann, Anja; Lilie, Hauke et al.
in: EMBO molecular medicine, Jahrgang 1, Nr. 1, 26.03.2009, S. 37-49.

Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review

Kirstein, J, Hoffmann, A, Lilie, H, Schmidt, R, Helga, RW, Heike, BO, Mogk, A & Turgay, K 2009, 'The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease', EMBO molecular medicine, Jg. 1, Nr. 1, S. 37-49. https://doi.org/10.1002/emmm.200900002
Kirstein, J., Hoffmann, A., Lilie, H., Schmidt, R., Helga, R. W., Heike, B. O., Mogk, A., & Turgay, K. (2009). The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease. EMBO molecular medicine, 1(1), 37-49. https://doi.org/10.1002/emmm.200900002
Kirstein J, Hoffmann A, Lilie H, Schmidt R, Helga RW, Heike BO et al. The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease. EMBO molecular medicine. 2009 Mär 26;1(1):37-49. doi: 10.1002/emmm.200900002
Kirstein, Janine ; Hoffmann, Anja ; Lilie, Hauke et al. / The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease. in: EMBO molecular medicine. 2009 ; Jahrgang 1, Nr. 1. S. 37-49.
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abstract = "A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degradation. Here, we analyse the molecular mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hspi00 adenosine triphosphatases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.",
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AU - Kirstein, Janine

AU - Hoffmann, Anja

AU - Lilie, Hauke

AU - Schmidt, Ronny

AU - Helga, Rubsamen Waigmann

AU - Heike, Brötz Oesterhelt

AU - Mogk, Axel

AU - Turgay, Kürşad

N1 - Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2009/3/26

Y1 - 2009/3/26

N2 - A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degradation. Here, we analyse the molecular mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hspi00 adenosine triphosphatases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.

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