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Dysregulation of Human Mitochondrial ClpP Protease Activity by Acyldepsipeptides Analogs Leads to Apoptotic Cell Death
Author(s) -
Houry Walid A.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.653.3
Subject(s) - apoptosis , protease , caspase , programmed cell death , cytotoxic t cell , cancer cell , biology , cell culture , microbiology and biotechnology , mitochondrion , chemistry , cancer , biochemistry , enzyme , genetics , in vitro
Acyldepsipeptides (ADEPs) are potential novel antibiotics. They dysregulate the activity of the highly conserved tetradecameric bacterial ClpP protease leading to bacterial cell death. Here, we identified several ADEP analogs that are potent dysregulators of the human mitochondrial ClpP (HsClpP). These ADEPs interact tightly with HsClpP causing the protease to non‐specifically degrade model substrates. Dysregulation of HsClpP activity by these ADEPs was found to have cytotoxic effects in multiple human cell lines as a result of the activation of the intrinsic, caspase‐dependent apoptosis. ADEP‐HsClpP co‐crystal structure was solved for one of the analogs revealing a highly complementary binding interface formed by two HsClpP neighbouring subunits but, unexpectedly, with HsClpP in the compact conformation. Given that HsClpP is highly expressed in multiple cancers and has important roles in cell metastasis, our findings suggest a novel therapeutic potential for ADEPs in cancer treatment. Support or Funding Information This work was funded by Natural Sciences and Engineering Research Council of Canada grant (RGPIN 2014‐05393) to WAH This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .