Accessibility Skip to Global Navigation Skip to Local Navigation Skip to Content Skip to Search Skip to Site Map Menu

Otago Medical School staff profiles

Dr Peter Mace

PositionSenior Lecturer
DepartmentDepartment of Biochemistry
QualificationsBSc(Hons) PhD
Research summaryMolecular signalling mechanisms at the interface between cellular life and death

Research

In our research we aim to understand signalling networks that regulate how cells respond to stress. We are particularly interested in how phosphorylation and ubiquitination act as protein switches to control cell death and proliferation. The main tools we employ are X-ray crystallography, biochemistry and biophysics, as well as collaborating with specialists in chemistry, cell biology and genetics. The overall goals of our research are to decipher how specific proteins are regulated in normal and diseased cells, and to translate this knowledge into more effective disease therapy.

We currently have three major projects studying molecular mechanisms that are disregulated in cancer and inflammatory diseases.

Stress-activated MAP kinase signalling

ASK SAXs

Our recent biochemical and structural studies of Apoptosis signal-regulating kinase 1 (ASK1) have uncovered several important features that control ASK1 activity (Weijman et al., 2017). These include a novel fold adjacent to the ASK1 kinase domain domain that facilitates substrate phosphorylation, as well as autoinhibition by the N-terminal domains of ASK1. In future work we aim to understand more about how this regulation may be disrupted under conditions of cellular stress, and how ASK proteins regulate inflammatory signalling in diseases such as non-alcoholic steatohepatitis.

Transcriptional regulation Tribbles pseudokinases

TRIB multistate

We have solved the first structures of a Tribbles pseudokinase (TRIB1), which can drive leukaemia development and is overexpressed across a range of other cancers (Murphy et al., 2015). Our experiments showed the basis for loss of ATP binding by the pseudokinase fold, how TRIB1 sequesters its own C-terminal tail from binding to ubiquitin ligases, and the specific sequence used by TRIB1 to recognise substrates. Subsequently we have solved the structure of TRIB1 bound to a key substrate, C/EBPɑ (Jamieson et al, 2018). In complex with C/EBPɑ, it becomes clear that substrate binding triggers conformational changes in TRIB1 that could potentially targeted by small molecules.

Epigenetic regulation by the Polycomb Repressive-Deubiquitinase complex

Ubiquitination of histone 2A is a key epigenetic modification characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Mutations in the human PR-DUB predispose to specific tumours, and occur sporadically in many types of cancer. Our structure-function studies of the PR-DUB complexes from Drosophila show that a bidentate (2:2 complex) is required for optimal activity (Foglizzo et al., 2018). Our findings suggest that increased local concentration at specific genomic loci drive PR-DUB assembly, and full activation of the complex, which is the subject of ongoing studies.

Calypso nucleosome

Our work is supported by generous grants from the Health Research Council of New Zealand, Lotteries Health Research New Zealand, the University of Otago, and previously by a Rutherford Discovery Fellowship administered by the Royal Society of New Zealand, and the Neuroligical Foundation of New Zealand.

Publications

Foglizzo, M., Middleton, A. J., Burgess, A. E., Crowther, J. M., Dobson, R. C. J., Murphy, J. M., Day, C. L., & Mace, P. D. (2018). A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes. Nature Communications, 9, 3932. doi: 10.1038/s41467-018-06186-1

Jamieson, S. A., Ruan, Z., Burgess, A. E., Curry, J. R., McMillan, H. D., Brewster, J. L., Dunbier, A. K., … Mace, P. D. (2018). Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Science Signaling, 11(549), eaau0597. doi: 10.1126/scisignal.aau0597

Weijman, J. F., Kumar, A., Jamieson, S. A., King, C. M., Caradoc-Davies, T. T., Ledgerwood, E. C., … Mace, P. D. (2017). Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1. PNAS, 114(11), E2096-E2105. doi: 10.1073/pnas.1620813114

Lechtenberg, B. C., Rajput, A., Sanishvili, R., Dobaczewska, M. K., Ware, C. F., Mace, P. D., & Riedl, S. J. (2016). Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature, 529, 546-550. doi: 10.1038/nature16511

Murphy, J. M., Nakatani, Y., Jamieson, S. A., Dai, W., Lucet, I. S., & Mace, P. D. (2015). Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure, 23(11), 2111-2121. doi: 10.1016/j.str.2015.08.017

Journal - Research Article

Jamieson, S. A., Ruan, Z., Burgess, A. E., Curry, J. R., McMillan, H. D., Brewster, J. L., Dunbier, A. K., … Mace, P. D. (2018). Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Science Signaling, 11(549), eaau0597. doi: 10.1126/scisignal.aau0597

Foglizzo, M., Middleton, A. J., Burgess, A. E., Crowther, J. M., Dobson, R. C. J., Murphy, J. M., Day, C. L., & Mace, P. D. (2018). A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes. Nature Communications, 9, 3932. doi: 10.1038/s41467-018-06186-1

Murphy, J. M., Mace, P. D., & Eyers, P. A. (2017). Live and let die: Insights into pseudoenzyme mechanisms from structure. Current Opinion in Structural Biology, 47, 95-104. doi: 10.1016/j.sbi.2017.07.004

Filipčík, P., Curry, J. R., & Mace, P. D. (2017). When worlds collide: Mechanisms at the interface between phosphorylation and ubiquitination. Journal of Molecular Biology, 429(8), 1097-1113. doi: 10.1016/j.jmb.2017.02.011

Weijman, J. F., Kumar, A., Jamieson, S. A., King, C. M., Caradoc-Davies, T. T., Ledgerwood, E. C., … Mace, P. D. (2017). Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1. PNAS, 114(11), E2096-E2105. doi: 10.1073/pnas.1620813114

Lechtenberg, B. C., Rajput, A., Sanishvili, R., Dobaczewska, M. K., Ware, C. F., Mace, P. D., & Riedl, S. J. (2016). Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature, 529, 546-550. doi: 10.1038/nature16511

Murphy, J. M., Nakatani, Y., Jamieson, S. A., Dai, W., Lucet, I. S., & Mace, P. D. (2015). Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure, 23(11), 2111-2121. doi: 10.1016/j.str.2015.08.017

Mace, P. D., Wallez, Y., Egger, M. F., Dobaczewska, M. K., Robinson, H., Pasquale, E. B., & Riedl, S. J. (2013). Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nature Communications, 4, 1681. doi: 10.1038/ncomms2687

More publications...