Prof Peter Czabotar, Division Head | WEHI Researcher Profile

About

The main focus of our research is to understand the control of cell death at the molecular level and to design therapeutics to target these pathways in disease settings.

One of these cell death pathways is called apoptosis and is regulated by the Bcl-2 family of proteins. In the past we have focused on how “guardian” proteins from the family keep the cell alive. Using information gleaned from our atomic characterization of these proteins we have worked with medicinal chemist colleagues to develop compounds to kill cancerous cells. Such drugs, so called BH3 mimetics, are now in the clinic for the treatment of CLL and AML, with the potential for other compounds to target family members in other cancer settings.

More recently we have switched our focus to the executioner members of the Bcl-2 family that are responsible for telling the cell to die. Our studies have revealed how executioners are activated and transformed into the entities that kill the cell. We now aim to use that information to develop drugs that can keep cells alive in setting such as stroke or neurodegenerative disorders in which tissue damage occurs to excessive cell death.

We are also exploring how the protein MLKL regulates a different type of cell death called necroptosis. After a necroptotic stimuli, MLKL is activated and ruptures the cell’s membrane, resulting in the release of inflammatory signals. As such, drugs that target MLKL have the potential to be useful for the treatment of inflammatory diseases.

We use structural biology, in particular protein crystallography and CryoEM, supported by biochemical and biological analyses, to decipher these cell death pathways. These tools allow us to observe the atomic details of cell death proteins, providing key insights into how they function at the molecular level and informing the development of therapeutic compounds capable of modulating their activity.

We also use these techniques to study other proteins important to human health, including: DNA binding proteins that are potential cancer therapeutic targets, SARS-CoV-2 proteins important for viral replication, and malarial proteins involved in parasite invasion of red blood cells.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof Peter Czabotar

2024;

Davies KA, Czabotar PE, Murphy JM. Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis. Current Opinion in Structural Biology. 2024;88:10.1016/j.sbi.2024.102891

Miller MS, Cowan AD, Brouwer JM, Smyth ST, Peng L, Wardak AZ, Uren RT, Luo C, Roy MJ, Shah S, Tan Z, Reid GE, Colman PM, Czabotar PE. Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids. The FEBS Journal. 2024;291(11):10.1111/febs.17031

Subas Satish HP, Iyer S, Shi MX, Wong AW, Fischer KC, Wardak AZ, Lio D, Brouwer JM, Uren RT, Czabotar PE, Miller MS, Kluck RM. A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells. Cell Death & Differentiation. 2024;31(6):10.1038/s41418-024-01289-3

Yuan Z, van Delft MF, Li MX, Sumardy F, Smith BJ, Huang DCS, Lessene G, Khakam Y, Jin R, He S, Smith NA, Birkinshaw RW, Czabotar PE, Dewson G. Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis. PLOS Biology. 2024;22(5):10.1371/journal.pbio.3002617

Meng Y, Garnish SE, Davies KA, Black KA, Leis AP, Horne CR, Hildebrand JM, Hoblos H, Fitzgibbon C, Young SN, Dite T, Dagley LF, Venkat A, Kannan N, Koide A, Koide S, Glukhova A, Czabotar PE, Murphy JM. Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization. Nature Communications. 2023;14(1):10.1038/s41467-023-42255-w

Czabotar PE, Garcia-Saez AJ. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nature Reviews Molecular Cell Biology. 2023;24(10):10.1038/s41580-023-00629-4

Birkinshaw RW, Iyer S, Lio D, Luo C, Brouwer J, Miller MS, Robin A, Uren RT, Dewson G, Kluck RM, Colman PM, Czabotar PE. The crystal structure of detergent-activated BAK dimers provides insights into BAK activation steps and how they stabilise membrane pores. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s205327332308912x

Miller MS, Subas-Satish H, Iyer S, Wardak AZ, Lio D, Shi MX, Wong A, Uren R, Brouwer JM, Czabotar PE, Kluck RM. Structure of the BAK- inhibiting antibody 14G6 bound to BAK identifies core–latch separation and α1-dissociation as essential events in BAK activation. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086709

Davies K, Meng Y, Fitzgibbon C, Young S, Garnish S, Horne C, Luo C, Garnier J, Liang L, Cowan A, Samson A, Lessene G, Sandow J, Czabotar P, Murphy J. Dissecting the RIPK3/MLKL necroptotic molecular switch. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323087788