Mutation analysis of the interactions between Mycobacterium tuberculosis caseinolytic protease C1 (ClpC1) and ecumicin

Jung, In-Pil; Ha, Na-Reum; Kim, A-Ru; Kim, Sang‐Heon; Yoon, Moon‐Young

doi:10.1016/j.ijbiomac.2017.03.126

Cited by 15 publications

(16 citation statements)

References 18 publications

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“…8; Table 5). ClpC1, especially the N -terminal domain (NTD), is highly conserved among mycobacteria (30). The ClpC1 constructs tested were found to be 100% genetically identical in the NTD but varied by several residues in other regions of the protein.…”

Section: Resultsmentioning

confidence: 99%

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus

Choules

Wolf

Lee

et al. 2019

Antimicrob Agents Chemother

123

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ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act on this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tuberculosis through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tuberculosis (MIC, 0.02 μM) and Mycobacterium abscessus (MIC, 0.4 μM). Spontaneously generated mutants resistant to RUFI involved seven unique single nucleotide polymorphism (SNP) mutations at three distinct codons within the N-terminal domain of clpC1 (V13, H77, and F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, while having no significant effect on the ATPase activity of ClpC1. This represents a marked difference from ecumicin, which inhibits ClpC1 proteolysis but stimulates the ATPase activity, thereby providing evidence that although these peptides share ClpC1 as a macromolecular target, their downstream effects are distinct, likely due to differences in binding.

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Section: Resultsmentioning

confidence: 99%

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus

Choules

Wolf

Lee

et al. 2019

Antimicrob Agents Chemother

123

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show abstract

“…CymA is smaller as compared with Ecumicin/Lassomycin, rationalizing different binding modes as their interaction sites in the ClpC1-NTD are not identical. For instance, Arg83 is essential for Ecumicin but not CymA binding (Figure S7B) (Jung et al, 2017;Vasudevan et al, 2013). Furthermore, Ecumicin does not bind to the isolated Mtb ClpC1-NTD in contrast to CymA (Weinhaupl et al, 2018).…”

Section: Discussionmentioning

confidence: 98%

Toxic Activation of an AAA+ Protease by the Antibacterial Drug Cyclomarin A

Maurer

Linder

Franke

et al. 2019

Cell Chemical Biology

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“…1b). When tested in vitro, ecumicin increases ClpC1 ATPase activity severalfold while simultaneously compromising the degradation of ClpC1P1P2 substrates (10,12). Lassomycin, an actinomycetes ribosomally encoded cyclic peptide, is yet another natural antibiotic able to kill Mtb persisters with efficiency (11).…”

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confidence: 99%

The antibiotic cyclomarin blocks arginine-phosphate–induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis

Weinhäupl

Brennich

Kazmaier

et al. 2018

Journal of Biological Chemistry

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can remain dormant in the host, an ability that explains the failure of many current tuberculosis treatments. Recently, the natural products cyclomarin, ecumicin, and lassomycin have been shown to efficiently kill persisters. Their target is the N-terminal domain of the hexameric AAA+ ATPase ClpC1, which recognizes, unfolds, and translocates protein substrates, such as proteins containing phosphorylated arginine residues, to the ClpP1P2 protease for degradation. Surprisingly, these antibiotics do not inhibit ClpC1 ATPase activity, and how they cause cell death is still unclear. Here, using NMR and small-angle X-ray scattering, we demonstrate that arginine-phosphate binding to the ClpC1 N-terminal domain induces millisecond dynamics. We show that these dynamics are caused by conformational changes and do not result from unfolding or oligomerization of this domain. Cyclomarin binding to this domain specifically blocked these N-terminal dynamics. On the basis of these results, we propose a mechanism of action involving cyclomarin-induced restriction of ClpC1 dynamics, which modulates the chaperone enzymatic activity leading eventually to cell death.

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Mutation analysis of the interactions between Mycobacterium tuberculosis caseinolytic protease C1 (ClpC1) and ecumicin

Cited by 15 publications

References 18 publications

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus

Toxic Activation of an AAA+ Protease by the Antibacterial Drug Cyclomarin A

The antibiotic cyclomarin blocks arginine-phosphate–induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis

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