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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Gersch, M; Famulla, K; Dahmen, M; Göbl, C; Malik, I; Richter, K; Korotkov, VS; Sass, P; Rübsamen-Schaeff, H; Madl, T; Brötz-Oesterhelt, H; Sieber, SA.
AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control.
Nat Commun. 2015; 6(2):6320-6320 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Madl Tobias
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Abstract:
The Clp protease complex degrades a multitude of substrates, which are engaged by a AAA+ chaperone such as ClpX and subsequently digested by the dynamic, barrel-shaped ClpP protease. Acyldepsipeptides (ADEPs) are natural product-derived antibiotics that activate ClpP for chaperone-independent protein digestion. Here we show that both protein and small-molecule activators of ClpP allosterically control the ClpP barrel conformation. We dissect the catalytic mechanism with chemical probes and show that ADEP in addition to opening the axial pore directly stimulates ClpP activity through cooperative binding. ClpP activation thus reaches beyond active site accessibility and also involves conformational control of the catalytic residues. Moreover, we demonstrate that substoichiometric amounts of ADEP potently prevent binding of ClpX to ClpP and, at the same time, partially inhibit ClpP through conformational perturbance. Collectively, our results establish the hydrophobic binding pocket as a major conformational regulatory site with implications for both ClpXP proteolysis and ADEP-based anti-bacterial activity.
Find related publications in this database (using NLM MeSH Indexing)
Allosteric Site -
Bacterial Proteins - chemistry
Binding Sites -
Calorimetry -
Catalysis -
Catalytic Domain -
Chromatography -
Depsipeptides - chemistry
Endopeptidase Clp - chemistry
Escherichia coli - chemistry
Fluorescein-5-isothiocyanate -
Hydrophobic and Hydrophilic Interactions -
Kinetics -
Light -
Listeria monocytogenes - chemistry
Mass Spectrometry -
Molecular Chaperones - chemistry
Mutation -
Protein Binding -
Protein Conformation -
Protein Structure, Secondary -
Staphylococcus aureus - chemistry
Substrate Specificity -

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