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

Research output: Contribution to journal › Article › Research › peer review

Authors

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

External Research Organisations

  • Freie Universität Berlin (FU Berlin)
  • Heidelberg University
  • Martin Luther University Halle-Wittenberg
  • AiCuris GmbH and Co. KG
View graph of relations

Details

Original languageEnglish
Pages (from-to)37-49
Number of pages13
JournalEMBO molecular medicine
Volume1
Issue number1
Publication statusPublished - 26 Mar 2009
Externally publishedYes

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.

Keywords

    ADEP, Antibiotic, Clp proteins, ClpP, Hsp100, Proteolysis

ASJC Scopus subject areas

Cite this

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, Vol. 1, No. 1, 26.03.2009, p. 37-49.

Research output: Contribution to journal › Article › Research › 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, vol. 1, no. 1, pp. 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 Mar 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 ; Vol. 1, No. 1. pp. 37-49.
Download
@article{01221012d7664e6a9e4f6fb531976bd3,
title = "The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease",
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.",
keywords = "ADEP, Antibiotic, Clp proteins, ClpP, Hsp100, Proteolysis",
author = "Janine Kirstein and Anja Hoffmann and Hauke Lilie and Ronny Schmidt and Helga, {Rubsamen Waigmann} and Heike, {Br{\"o}tz Oesterhelt} and Axel Mogk and K{\"u}r{\c s}ad Turgay",
note = "Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2009",
month = mar,
day = "26",
doi = "10.1002/emmm.200900002",
language = "English",
volume = "1",
pages = "37--49",
journal = "EMBO molecular medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "1",

}

Download

TY - JOUR

T1 - The antibiotic ADEP reprogrammes CIpP, switching it from a regulated to an uncontrolled protease

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.

AB - 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.

KW - ADEP

KW - Antibiotic

KW - Clp proteins

KW - ClpP

KW - Hsp100

KW - Proteolysis

UR - http://www.scopus.com/inward/record.url?scp=71749110235&partnerID=8YFLogxK

U2 - 10.1002/emmm.200900002

DO - 10.1002/emmm.200900002

M3 - Article

AN - SCOPUS:71749110235

VL - 1

SP - 37

EP - 49

JO - EMBO molecular medicine

JF - EMBO molecular medicine

SN - 1757-4676

IS - 1

ER -