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.
Left: 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.
Below: 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.
Enquires from prospective graduate students are welcome. Information about scholarships for postgraduate students is available at the University of Otago's website http://www.otago.ac.nz/postgraduate/index.html
Johannes F Weijman, Stefan J Riedl, and Peter D Mace., Structural Studies of ERK2 Protein Complexes., Methods in Molecular Biology. New York, NY 2017 vol. 1487 (Chapter 4) pp. 53-63., Link »
Joshua D Wright, Peter D Mace, and Catherine L Day., Noncovalent Ubiquitin Interactions Regulate the Catalytic Activity of Ubiquitin Writers., Trends Biochem Sci 2016., Link »
Bernhard C Lechtenberg, Akhil Rajput, Ruslan Sanishvili, Małgorzata K Dobaczewska, Carl F Ware, Peter D Mace, and Stefan J Riedl., Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation., Nature 2016, Link »
Joshua D Wright, Peter D Mace, and Catherine L Day., Secondary ubiquitin-RING docking enhances Arkadia and Ark2C E3 ligase activity., Nat Struct Mol Biol 2015., Link »
James M Murphy, Yoshio Nakatani, Sam A Jamieson, Weiwen Dai, Isabelle S Lucet, and Peter D Mace., Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase., Structure 2015 vol. 23 (11) pp. 2111-2121, Link »
Bernhard C Lechtenberg, Peter D Mace, and Stefan J Riedl, Structural mechanisms in NLR inflammasome signaling., Current Opinion in Structural Biology 2014 vol. 29C pp. 17-25, Link »
Peter D Mace, Stefan J Riedl, and Guy S Salvesen, Caspase Enzymology and Activation Mechanisms., Methods in enzymology 2014 vol. 544C pp. 161-178, Link »
R Feltham, B Bettjeman, R Budhidarmo, P D Mace, S Shirley, S.M. Condon, S.K. Chunduru, M.A. McKinlay, D L Vaux, J Silke, and C L Day, Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization, The Journal of Biological Chemistry 2011 vol. 286 (19) pp. 17015-17028,
Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB, Riedl SJ (2013) Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nature Communications. 4, 1681.
Proell M, Gerlic M, Mace PD, Reed JC, Riedl SJ (2013) The CARD plays a critical role in ASC foci formation and inflammasome signaling. Biochemical Journal. 449, 613-21.
Wallez Y, Mace PD, Pasquale EB, Riedl SJ (2012) NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer. Genes & Cancer. 3, 38293.
Mace PD, Wallez Y, Dobaczewska MK, Lee JJ, Robinson H, Pasquale EB, Riedl SJ (2011) NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling. Nature Structural & Molecular Biology. 18, 1381-7.
Mace PD, Riedl SJ (2010) Molecular Cell Death Platforms and Assemblies. Current Opinion in Cell Biology. 22, 82836.
Mace PD, Smits C, Vaux DL, Silke J, Day CL (2010) Asymmetric Recruitment of cIAPs by TRAF2. Journal of Molecular Biology. 400, 815.
Mace PD, Shirley S, Day CL (2009) Assembling the building blocks: structure and function of inhibitor of apoptosis proteins. Cell Death & Differentiation. 17, 4653.
Mace PD, Linke K, Feltham R, Schumacher FR, Smith CA, Vaux DL, Silke J, Day CL (2008) Structures of the cIAP2 RING Domain Reveal Conformational Changes Associated with Ubiquitin-conjugating Enzyme (E2) Recruitment. Journal of Biological Chemistry. 283, 3163340.
Linke K*, Mace PD*, Smith CA, Vaux DL, Silke J, Day CL (2008) Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death & Differentiation. 15, 8418. *Joint first authors
Mace PD, Cutfield JF, Cutfield SM (2006) High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: implications for ligand binding. Biochemical & Biophysical Research Communications. 351, 8318.