Please use this identifier to cite or link to this item: doi:10.22028/D291-35225
Title: Generation of Lasso Peptide-Based ClpP Binders
Author(s): Malik, Imran T.
Hegemann, Julian D.
Brötz-Oesterhelt, Heike
Language: English
Title: International Journal of Molecular Sciences
Volume: 23 (2022)
Issue: 1
Publisher/Platform: MDPI
Year of Publication: 2021
Free key words: Clp protease
Clp ATPase
lasso peptide
epitope grafting
natural product
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: The Clp protease system fulfills a plethora of important functions in bacteria. It consists of a tetradecameric ClpP barrel holding the proteolytic centers and two hexameric Clp-ATPase rings, which recognize, unfold, and then feed substrate proteins into the ClpP barrel for proteolytic degradation. Flexible loops carrying conserved tripeptide motifs protrude from the Clp-ATPases and bind into hydrophobic pockets (H-pockets) on ClpP. Here, we set out to engineer microcin J25 (MccJ25), a ribosomally synthesized and post-translationally modified peptide (RiPP) of the lasso peptide subfamily, by introducing the conserved tripeptide motifs into the lasso peptide loop region to mimic the Clp-ATPase loops. We studied the capacity of the resulting lasso peptide variants to bind to ClpP and affect its activity. From the nine variants generated, one in particular (12IGF) was able to activate ClpP from Staphylococcus aureus and Bacillus subtilis. While 12IGF conferred stability to ClpP tetradecamers and stimulated peptide degradation, it did not trigger unregulated protein degradation, in contrast to the H-pocket-binding acyldepsipeptide antibiotics (ADEPs). Interestingly, synergistic interactions between 12IGF and ADEP were observed.
DOI of the first publication: 10.3390/ijms23010465
URL of the first publication:
Link to this record: urn:nbn:de:bsz:291--ds-352250
ISSN: 1422-0067
Date of registration: 28-Feb-2023
Description of the related object: Supplementary Materials
Related object:
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Keiner Professur zugeordnet
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

Files for this record:
File Description SizeFormat 
ijms-23-00465-v2.pdf2,37 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons