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Department of Biochemistry profile

Dr Peter Mace

PositionSenior Research Fellow
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 multiple active projects studying proteins that are disregulated in cancer, neurological conditions and kidney disease. Two examples are understanding signalling by Tribbles pseudokinases and regulation of MAP kinase signalling cascades.

Scientific image.
We recently 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 (peach colour), how TRIB1 sequesters its own C-terminal tail (grey) from binding to ubiquitin ligases, and the specific sequence used by TRIB1 to recognise substrates.

Scientific image.
Our recent biochemical and structural studies of Apoptosis signal-regulating kinase 1 (ASK1) were able to uncover several important features that control ASK1 activity. These include a novel fold (yellow/purple) adjacent to the ASK1 kinase domain (green) domain that facilitate 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.

Positions

Enquires from prospective graduate students are welcome. Information about scholarships for postgraduate students is available at the University of Otago's website otago.ac.nz/postgraduate.

Publications

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. Advance online publication. doi: 10.1073/pnas.1620813114

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

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, 25(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

Journal - Research Article

Filipčík, P., Curry, J. R., & Mace, P. D. (2017). When worlds collide: Mechanisms at the interface between phosphorylation and ubiquitination. Journal of Molecular Biology. Advance online publication. 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. Advance online publication. 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, 25(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...