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

Author(s):Show less -

Wong, Keith S. ^[1] ; Mabanglo, Mark F. ^[1] ; Seraphim, Thiago V. ^{[1, 2]} ; Mollica, Antonio ^{[1, 3]} ; Mao, Yu-Qian ^[1] ; Rizzolo, Kamran ^[1] ; Leung, Elisa ^[1] ; Moutaoufik, Mohamed T. ^[2] ; Hoell, Larissa ^[2] ; Phanse, Sadhna ^[2] ; Goodreid, Jordan ^[4] ; Barbosa, Leandro R. S. ^[5] ; Ramos, Carlos H. I. ^[6] ; Babu, Mohan ^[2] ; Mennella, Vito ^{[1, 3]} ; Batey, Robert A. ^[4] ; Schimmer, Aaron D. ^[7] ; Houry, Walid A. ^{[4, 1]}

Affiliation

^[1] Univ Toronto, Dept Biochem, MaRS Ctr, 661 Univ Ave, West Tower, Room 1612, Toronto, ON M5G 1M1 - Canada

^[2] Univ Regina, Dept Biochem, Regina, SK S4S 0A2 - Canada

^[3] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 0A4 - Canada

^[4] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6 - Canada

^[5] Univ Sao Paulo, Inst Phys, BR-05508090 Sao Paulo, SP - Brazil

^[6] Univ Campinas UNICAMP, Inst Chem, BR-13083970 Campinas, SP - Brazil

^[7] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9 - Canada

• Document type: Journal article
• Source: Cell Chemical Biology; v. 25, n. 8, p. 1017+, AUG 16 2018.
• Web of Science Citations: 9

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. (AU)

• FAPESP's process: 16/05019-0 - The thermodynamical and structural influence of ionic liquids in biomimetic membrane models
• Grantee: Natália Fernandes de Oliveira
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 12/01953-9 - Proteins under fibrillation process: a structural and spectroscopic study of the influence of denaturating agents
• Grantee: Leandro Ramos Souza Barbosa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/15822-1 - Physicochemical and structural properties of Ionic Liquids and drugs interacting with biologicaly relevant systems.
• Grantee: Leandro Ramos Souza Barbosa
• Support Opportunities: Regular Research Grants