Our research program uses biochemical, cell biological and structural approaches to examine how the BCL-2 protein family regulates the mitochondrial pathway of apoptosis.

We are particularly interested in how two pore-forming BCL-2 family members, BAX and BAK, undergo conformation change and generate pores in the mitochondrial outer membrane. The goal of our research is to identify new means of specifically regulating apoptotic cell death in cancer and other diseases.

We have found that following major conformation changes, both BAX and BAK form unusual symmetric homodimers that act as the basic unit of the apoptotic pore, and are using different strategies to determine how dimers form clusters that disrupt the membrane.

We also discovered that BAK can be activated by antibodies, and are testing whether these antibodies can be delivered into cancer cells to directly trigger BAK-mediated apoptosis.

Scientific figure
We are investigating the steps involved in apoptotic pore formation in the mitochondrial outer membrane by the BAK and BAX proteins


Selected publications from A/Prof Ruth Kluck

Hockings, C, Alsop, AE, Fennell, SC, Lee, EF, Fairlie, WD, Dewson, G, and KLUCK, RM. Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins. Cell Death Differ. 2018. 25, 719-732. PMID: 29459767

Uren RT, O’Hely M, Iyer S, Bartolo R, Shi MX, Brouwer JM, Alsop AE, Dewson G, Kluck RM. Disordered clusters of Bak dimers rupture mitochondria during apoptosis. Elife 2017. 6 e19944 PMID: 28182867

Iyer S, Anwari K, Alsop AE, Yuen WS, Huang DC, Carroll J, Smith NA, Smith BJ, Dewson G, Kluck RM. Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies. Nat Commun. 2016. 7, 117342 PMID: 27217060

Alsop AE, Fennell SC, Bartolo RC, Tan IK, Dewson G, Kluck RM. Dissociation of Bak alpha1 helix from the core and latch domains is required for apoptosis. Nat Commun. 2015. 6, 6841 PMID: 25880232

Westphal D, Dewson G, Menard M, Frederick P, Iyer S, Bartolo R, Gibson L, Czabotar PE, Smith BJ, Adams JM, Kluck RM. Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane. PNAS. Vol 111, issue 39, E4076-85. PMID: 25228770

Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. Cell. 2013 Jan 31; 152(3):519-531. PMID: 23374347

Westphal D, Dewson G, Czabotar PE, Kluck RM. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2011 Apr; 1813(4):521-531. PMID: 21195116

Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol Cell. 2009 Nov 25;36(4):696-703. PMID 19941828

Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol Cell. 2008 May 9;30(3):369-80 PMID: 18471982

Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997 Feb 21;275(5303):1132-6 PMID: 90273151

Lab research projects

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