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.
Australia, The University of Queensland, BSc, PhD
2011 Future Fellowship, Australian Research Council
2002 Wellcome Trust Overseas Senior Research Fellowship
2017 Leukemia & Lymphoma Society, US
2012, 2017 Program Grants, National Health and Medical Research Council
2011 Future Fellowship, Australian Research Council
2009, 2010, 2011 Project Grants, National Health and Medical Research Council
2014- Advisory Board Member, Gene Technology Access Centre
2015- Editorial Board, Scientific Reports
2011- Editorial Board, Cell Death & Disease
2010-15 Faculty of 1000 Contributing Member
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
A key event in apoptotic cell death is the oligomerisation of the BAX and BAK proteins to form pores in mitochondria, although how they form pores is still unclear.
We recently found that cells lacking the putative trafficking protein PACS1 are resistant to apoptosis due to unusual complexes of BAX and BAK (Brasacchio et al, Cell Death Differ, 2017).
We are thus characterising the unusual BAX and BAK complexes in PACS1-knockdown cells to understand this new means of resistance.
As the formation of BAX and BAK homo-oligomers strongly correlates with their ability to perforate mitochondria, defining how BAX and BAK dimers self-associate and interact with the membrane will reveal how they trigger apoptosis.
Our data indicate that dimers do not interact by distinct protein-protein interface, but form disordered clusters to generate pores (Uren et al, eLife, 2017; Uren et al, Philos Trans R Soc Lond B Biol Sci, 2017).
A range of biochemical approaches will examine further how the outer membrane is involved in oligomerisation of dimers.
Inhibition of apoptosis by prosurvival BCL-2 proteins contributes to oncogenesis and to resistance to cancer treatments. In particular, MCL-1 can cause resistance by sequestering activated BAK.
We aim to better understand when and how MCL-1 and BAK interact in different cancer cells following treatment, and so identify ways of circumventing this resistance.
We found that an antibody to the BAK protein can trigger its activation leading to mitochondrial pore formation and cell death (Iyer et al, Nat Commun 2016 7:11734).
To investigate if this antibody can be developed as a novel anti-cancer agent, this project will combine the anti-BAK antibody with others that can be taken up by cancer cells, and test for induction of cell death.