Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival

Hoi, David M.; Junker, Sabryna; Junk, Lukas; Schwechel, Kristin; Fischel, Katharina; Podlesainski, David; Hawkins, Paige M. E.; Geelen, Lasse van; Kaschani, Farnusch; Leodolter, Julia; Morreale, Francesca; Kleine, Stefan; Guha, Somraj; Rumpel, Klaus; Schmiedel, Volker Martin; Weinstabl, Harald; Meinhart, Anton; Payne, Richard J.; Kaiser, Markus; Hartl, Markus; Boehmelt, Guido; Kazmaier, Uli; Kalscheuer, Rainer; Clausen, Tim

doi:10.1016/j.cell.2023.04.009

Cited by 32 publications

(27 citation statements)

References 65 publications

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“…Increasing studies suggests that the Clp systems in cyanobacteria and plants are known to play a key role in regulating photosynthesis and metabolic processes. , Although the specific substrates and functions of the Clp systems in photosynthesis have not been extensively studied, their significance in regulating metabolic processes in bacteria and humans has been established. − The conceptual model derived from our study indicates that cyanobacteria exhibit mechanisms similar to those of bacteria, suggesting that the Clp system has the capability to regulate metabolism and photosynthesis in cyanobacteria. Previous studies demonstrated that the cyanobacterial Clp systems can regulate the degradation of several photosynthesis-related proteins, including β-phycocyanin, photosystem II PsbH protein, and cytochrome b 6f complex petC. , Our results also showed that a large proportion of proteins associated with photosynthesis were found to be the potential substrates of ClpX-targeted, ranging from light harvesting to photosystem I, photosystem II, and the ATPase complex.…”

Section: Discussionmentioning

confidence: 74%

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria

Liu,

Cai,

Zhang

et al. 2024

J. Proteome Res.

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Protein homeostasis is essential for cyanobacteria to maintain proper cellular function under adverse and fluctuating conditions. The AAA+ superfamily of proteolytic complexes in cyanobacteria plays a critical role in this process, including ClpXP, which comprises a hexameric ATPase ClpX and a tetradecameric peptidase ClpP. Despite the physiological effects of ClpX on growth and photosynthesis, its potential substrates and underlying mechanisms in cyanobacteria remain unknown. In this study, we employed a streptavidin− biotin affinity pull-down assay coupled with label-free proteome quantitation to analyze the interactome of ClpX in the model cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). We identified 503 proteins as potential ClpX-binding targets, many of which had novel interactions. These ClpX-binding targets were found to be involved in various biological processes, with particular enrichment in metabolic processes and photosynthesis. Using protein−protein docking, GST pull-down, and biolayer interferometry assays, we confirmed the direct association of ClpX with the photosynthetic proteins, ferredoxin-NADP + oxidoreductase (FNR) and phycocyanin subunit (CpcA). Subsequent functional investigations revealed that ClpX participates in the maintenance of FNR homeostasis and functionality in Synechocystis grown under different light conditions. Overall, our study provides a comprehensive understanding of the extensive functions regulated by ClpX in cyanobacteria to maintain protein homeostasis and adapt to environmental challenges.

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Section: Discussionmentioning

confidence: 74%

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria

Liu,

Cai,

Zhang

et al. 2024

J. Proteome Res.

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“…The ClpP system represents a unique type of serine protease complex responsible for the proteolysis of damaged or misfolded proteins that serves as a critical regulator of protein turnover and proteome homeostasis. ClpPs are involved in a range of human diseases and play a vital role in many bacterial infections; − therefore, interfering with ClpP function is regarded as a promising therapeutic strategy in the treatment of numerous disorders. , Herein, we identified cediranib as a novel structural class for MtbClpP1P2 inhibition with antitubercular activity in vitro. Using biophysical approaches, we evaluated the interactions between cediranib derivatives and MtbClpP1P2.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors

Yang,

Zhao,

et al. 2023

J. Med. Chem.

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“…The direct-to-proteasome degrader strategy has also been applied to create PROTACs that function in bacterial cells, which lack a Ubiquitin system. [44] It is also possible to make degraders that bypass E3 Ub ligases by engaging core constituents of the multi-protein E3 complexes, including the E2 Ub ligase, [45] rather than the substrate receptor subunits such as VHL or Cereblon (Figure 6C). In this scenario, the chemical dimerizer essentially performs the role of an E3 Ub ligase in a native Ubiquitylation reaction.…”

Section: Overcoming the Limitations Of Protacsmentioning

confidence: 99%

Catalytic Protein Inhibitors

Kodadek

2024

Angewandte Chemie

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Many of the highest priority targets in a wide range of disease states are difficult‐to‐drug proteins. The development of reversible small molecule inhibitors for the active sites of these proteins with sufficient affinity and residence time on‐target is an enormous challenge. This has engendered interest in strategies to increase the potency of a given protein inhibitor by routes other than further improvement is gross affinity. Amongst these, the development of catalytic protein inhibitors has garnered the most attention and investment, particularly with respect to protein degraders, which catalyze the destruction of the target protein. This article discusses the genesis of the burgeoning field of catalytic inhibitors, the current state of the art and exciting future directions.

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Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival

Cited by 32 publications

References 65 publications

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria

Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors

Catalytic Protein Inhibitors

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