Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death

Keith S Wong; Mark F Mabanglo; Thiago V Seraphim; Antonio Mollica; Yu-Qian Mao; Kamran Rizzolo; Elisa Leung; Mohamed T Moutaoufik; Larissa Hoell; Sadhna Phanse; Jordan Goodreid; Leandro R S Barbosa; Carlos H I Ramos; Mohan Babu; Vito Mennella; Robert A Batey; Aaron D Schimmer; Walid A Houry

doi:10.1016/j.chembiol.2018.05.014

Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death

Cell Chem Biol. 2018 Aug 16;25(8):1017-1030.e9. doi: 10.1016/j.chembiol.2018.05.014. Epub 2018 Jun 28.

Authors

Keith S Wong¹, Mark F Mabanglo¹, Thiago V Seraphim², Antonio Mollica³, Yu-Qian Mao¹, Kamran Rizzolo¹, Elisa Leung¹, Mohamed T Moutaoufik⁴, Larissa Hoell⁴, Sadhna Phanse⁴, Jordan Goodreid⁵, Leandro R S Barbosa⁶, Carlos H I Ramos⁷, Mohan Babu⁴, Vito Mennella³, Robert A Batey⁵, Aaron D Schimmer⁸, Walid A Houry⁹

Affiliations

¹ Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada.
² Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada; Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
³ Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
⁵ Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
⁶ Institute of Physics, University of São Paulo, São Paulo, São Paulo 05508-090 Brazil.
⁷ Institute of Chemistry, University of Campinas UNICAMP, Campinas, São Paulo 13083-970 Brazil.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
⁹ Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON M5G 1M1, Canada; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada. Electronic address: walid.houry@utoronto.ca.

PMID: 30126533
DOI: 10.1016/j.chembiol.2018.05.014

Abstract

Acyldepsipeptides (ADEPs) are potential antibiotics that dysregulate the activity of the highly conserved tetradecameric bacterial ClpP protease, leading to bacterial cell death. Here, we identified 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 ADEP was found to induce cytotoxic effects via 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 neighboring 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 therapeutic potential for ADEPs in cancer treatment.

Keywords: ClpP; acyldepsipeptides; apoptosis; dysregulation of protease; mitochondria; x-ray structure.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acylation
Anti-Bacterial Agents / adverse effects*
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology
Apoptosis / drug effects*
Bacterial Infections / drug therapy
Bacterial Infections / microbiology
Cell Line, Tumor
Depsipeptides / adverse effects*
Depsipeptides / chemistry*
Depsipeptides / pharmacology
Endopeptidase Clp / chemistry
Endopeptidase Clp / metabolism*
HEK293 Cells
Humans
Mitochondria / drug effects*
Mitochondria / enzymology
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / enzymology

Substances

Anti-Bacterial Agents
Depsipeptides
ClpP protein, human
Endopeptidase Clp

Abstract

Publication types

MeSH terms

Substances

Grants and funding