Research in our lab is aimed at understanding the regulation of signal transduction in mammalian cells. We are currently focusing on two specific pathways; the role of cytochrome c in the regulation of apoptosis, and redox regulation of mammalian cell signalling.
In collaboration with Professor Ian Morison we have identified the first naturally occurring mutation in cytochrome c, in a New Zealand family with mild thrombocytopenia (low platelets). This mutation enhances the activity of cytochrome c in the cell death pathway. By dysregulating platelet production in the bone marrow, the mutant protein causes premature release of platelets into the marrow space instead of into the circulation. We are characterising the molecular basis of this increased activity, and determining how this alters platelet production.
Crystal structure of human G41S cytochrome c
Model for the function of peroxiredoxins
Oxidants and free radicals have historically been considered harmful, causing damage to cells and being associated with disease. However over recent years it has become apparent that reactive oxygen species and shifts in redox equilibria can have beneficial as well as detrimental effects in cells. We are interested in understanding how alterations in redox equilibria translate into cellular outcomes. Hydrogen peroxide is a particularly important oxidant in cell signalling, and our data suggests that the peroxiredoxin family of peroxidases has an active role in converting peroxides into useful signals in mammalian cells, by catalysing disulfide bond formation in target proteins. The function and regulation of peroxiredoxins, and other antioxidant enzymes, is being investigated using inducible overexpression and knockdown of enzymes involved in the metabolism of reactive oxygen species (ROS) and analysing specific signalling pathways.
Enquires about projects from prospective graduate students and postdoctoral fellows are welcome.
Current PhD opportunities in the Ledgerwood lab.
Lily Ong, Ian M Morison, and Elizabeth C Ledgerwood., Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent and -independent processes., Br J Haematol 2016., Link »
Elizabeth C Ledgerwood, James W A Marshall, and Johannes F Weijman., The role of peroxiredoxin 1 in redox sensing and transducing., Archives of Biochemistry and Biophysics 2016., Link »
T M Josephs, M E Hibbs, L Ong, I M Morison, and E C Ledgerwood., Interspecies variation in the functional consequences of mutation of cytochrome c., PLoS ONE 2015 vol. 10 (6)., Link »
Tracy M Josephs, Ian M Morison, Catherine L Day, Sigurd M Wilbanks, and Elizabeth C Ledgerwood, Enhancing the peroxidase activity of cytochrome c by mutation of residue 41: implications for the peroxidase mechanism and cytochrome c release., The Biochemical journal 2014 vol. 458 (2) pp. 259-265, Link »
Tracy M Josephs, Matthew D Liptak, Gillian Hughes, Alexandra Lo, Rebecca M Smith, Sigurd M Wilbanks, Kara L Bren, and Elizabeth C Ledgerwood, Conformational change and human cytochrome c function: mutation of residue 41 modulates caspase activation and destabilizes Met-80 coordination., Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry , Link »
Reagan M Jarvis, Stephanie M Hughes, and Elizabeth C Ledgerwood, Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells., Free Radical Biology And Medicine Volume 53, Issue 7, 1 October 2012, Pages 15221530, Link »
Liptak, M.D., Fagerlund, R.D., Ledgerwood, E.C., Wilbanks, S.M. and Bren, K.L. The proapoptotic G41S mutation to human cytochrome c alters the heme electronic structure and increases the electron self-exchange rate Journal of the American Chemical Society133, 1153-1155 (2011)
Porteous, C.M., Logan, A., Evans, C., Ledgerwood, E.C., Menon, D.K., Aigbirhio, F., Smith, A.J. and Murphy, M.P. Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes Biochim Biophys Acta 1800, 1009-1017 (2010)
Westphal, D., Ledgerwood, E.C.#, Tyndall, J.D., Hibma, M.H., Ueda, N., Fleming, S.B. and Mercer, A.# The orf virus inhibitor of apoptosis functions in a Bcl-2-like manner, binding and neutralizing a set of BH3-only proteins and active Bax. Apoptosis 14, 1317-1330 (2009) (#joint senior authors)
Ledgerwood, E.C. and Morison, I.M. Targeting the apoptosome for cancer therapy. Clinical Cancer Research 15, 420-424 (2009)
Morison, I.M., Cramer-Bordé, E.M., Cheesman, E.J., Cheong, P.L., Holyoake, A.J., Fichelson, S., Weeks, R.J., Lo, A., Davies, S.M.K., Wilbanks, S.M., Fagerlund, R.D., Ludgate, M.W., da Silva Tatley, F.M., Coker, M.S.A., Bockett, N.A., Hughes, G., Pippig, D.A., Smith, M.P., Capron, C. and Ledgerwood, E.C. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nature Genetics 40, 387-389 (2008)
Cox, A. G., Pullar, J. M., Hughes, G., Ledgerwood, E. C. and Hampton, M. B. Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radical Biology and Medicine, 44: 1001-1009 (2008)
Jarvis, R.M., Göttert, J., Murphy, M.P. and Ledgerwood, E.C. Mitochondria-targeted antioxidants do not prevent tumour necrosis factor-induced necrosis of L929 cells Free Radical Research 41, 1041-1046 (2007)
Westphal, D., Ledgerwood, E.C., Hibma, M.H., Fleming, S.B., Whelan, E.M. and Mercer, A.A. A novel Bcl-2-like inhibitor of apoptosis is encoded by the parapoxvirus, Orf virus. Journal of Virology 81, 7178-7188 (2007)
Hughes, G., Murphy, M.P. and Ledgerwood, E.C. Mitochondrial reactive oxygen species regulate the temporal activation of Nuclear Factor kappa B to modulate Tumour Necrosis Factor-induced apoptosis: evidence from mitochondria-targeted antioxidants. Biochemical Journal 389, 83-89 (2005)
Kelso, G.F., Porteous, C.M., Hughes, G., Ledgerwood, E.C., Gane, A.M., Smith, R.A.J. and Murphy, M.P. Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants. Annals of the New York Academy of Sciences, 959, 263-274 (2002)
Kelso, G.F., Porteous, C.M., Coulter, C.V., Hughes, G., Porteous, W.K., Ledgerwood, E.C., Smith, R.A.J. and Murphy, M.P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. Journal of Biological Chemistry, 276, 45884596 (2001)
Scarlett, J.L., Sheard, P.W., Hughes, G., Ledgerwood, E.C., Ku, H-H. and Murphy, M.P. Changes in mitochondrial membrane potential during staurosporine-induced apoptosis in Jurkat cells. FEBS Letters, 475, 267-272 (2000)