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Department of Biochemistry profile

Dr Liz Ledgerwood

PositionSenior Lecturer
DepartmentDepartment of Biochemistry
QualificationsBSc(Hons), PhD
Research summaryApoptosis, signal transduction, redox regulation

Research

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.

Determining the role of cytochrome c in the regulation of apoptosis

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.

Scientific image.
Crystal structure of human G41S cytochrome c.

Redox regulation of mammalian cell signalling

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.

Scientific image.
Model for the function of peroxiredoxins.

Publications

Ledgerwood, E. C., Marshall, J. W. A., & Weijman, J. F. (2017). The role of peroxiredoxin 1 in redox sensing and transducing. Archives of Biochemistry & Biophysics, 617, 60-67. doi: 10.1016/j.abb.2016.10.009

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

Ong, L., Morison, I. M., & Ledgerwood, E. C. (2017). Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent and -independent processes. British Journal of Haematology, 176(2), 268-279. doi: 10.1111/bjh.14421

Josephs, T. M., Hibbs, M. E., Ong, L., Morison, I. M., & Ledgerwood, E. C. (2015). Interspecies variation in the functional consequences of mutation of cytochrome c. PLoS ONE, 10(6), e0130292. doi: 10.1371/journal.pone.0130292

Josephs, T. M., Morison, I. M., Day, C. L., Wilbanks, S. M., & Ledgerwood, E. C. (2014). Enhancing the peroxidase activity of cytochrome c by mutation of residue 41: Implications for the peroxidase mechanism and cytochrome c release. Biochemical Journal, 458(2), 259-265. doi: 10.1042/BJ20131386

Chapter in Book - Research

Ledgerwood, E. C., & Prins, J. B. (1999). Tumour necrosis factor alpha. In S. M. Marshall, P. D. Home & R. A. Rizza (Eds.), The Diabetes Annual. (12 ed.) (pp. 161-180). Amsterdam: Elsevier.

Ledgerwood, E. C., & Brennan, S. (1995). Furin. In A. Haeberli (Ed.), Human Protein Data: 3rd Instalment. VCH: Weinheim and New York.

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Journal - Research Article

Ledgerwood, E. C., Marshall, J. W. A., & Weijman, J. F. (2017). The role of peroxiredoxin 1 in redox sensing and transducing. Archives of Biochemistry & Biophysics, 617, 60-67. doi: 10.1016/j.abb.2016.10.009

Ong, L., Morison, I. M., & Ledgerwood, E. C. (2017). Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent and -independent processes. British Journal of Haematology, 176(2), 268-279. doi: 10.1111/bjh.14421

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

Josephs, T. M., Hibbs, M. E., Ong, L., Morison, I. M., & Ledgerwood, E. C. (2015). Interspecies variation in the functional consequences of mutation of cytochrome c. PLoS ONE, 10(6), e0130292. doi: 10.1371/journal.pone.0130292

Josephs, T. M., Morison, I. M., Day, C. L., Wilbanks, S. M., & Ledgerwood, E. C. (2014). Enhancing the peroxidase activity of cytochrome c by mutation of residue 41: Implications for the peroxidase mechanism and cytochrome c release. Biochemical Journal, 458(2), 259-265. doi: 10.1042/BJ20131386

Josephs, T. M., Liptak, M. D., Hughes, G., Lo, A., Smith, R. M., Wilbanks, S. M., … Ledgerwood, E. C. (2013). Conformational change and human cytochrome c function: Mutation of residue 41 modulates caspase activation and destabilizes Met-80 coordination. Journal of Biological Inorganic Chemistry, 18, 289-297. doi: 10.1007/s00775-012-0973-1

Jarvis, R. M., Hughes, S. M., & Ledgerwood, E. C. (2012). Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells. Free Radical Biology & Medicine, 53(7), 1522-1530. doi: 10.1016/j.freeradbiomed.2012.08.001

Bordé, E. C., Ouzegdouh, Y., Ledgerwood, E. C., & Morison, I. M. (2011). Congenital thrombocytopenia and cytochrome c mutation: A matter of birth and death. Seminars in Thrombosis & Hemostasis, 37(6), 664-672. doi: 10.1055/s-0031-1291376

Liptak, M. D., Fagerlund, R. D., Ledgerwood, E. C., Wilbanks, S. M., & Bren, K. (2011). 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 Society, 133(5), 1153-1155. doi: 10.1021/ja106328k

Porteous, C. M., Logan, A., Evans, C., Ledgerwood, E. C., Menon, D. K., Aigbirhio, F., Smith, R. A. J., & Murphy, M. P. (2010). Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes. Biochimica et Biophysica Acta: General Subjects, 1800(9), 1009-1017. doi: 10.1016/j.bbagen.2010.06.001

Ledgerwood, E. C., & Morison, I. M. (2009). Targeting the apoptosome for cancer therapy. Clinical Cancer Research, 15(2), 420-424. doi: 10.1158/1078-0432.CCR-08-1172

Westphal, D., Ledgerwood, E. C., Tyndall, J. D. A., Hibma, M. H., Ueda, N., Fleming, S. B., & Mercer, A. A. (2009). 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(11), 1317-1330. doi: 10.1007/s10495-009-0403-1

Cox, A. G., Pullar, J. M., Hughes, G., Ledgerwood, E. C., & Hampton, M. B. (2008). Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radical Biology & Medicine, 44(6), 1001-1009. doi: 10.1016/j.freeradbiomed.2007.11.017

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., … Ledgerwood, E. C. (2008). A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nature Genetics, 40(4), 387-389. doi: 10.1038/ng.103

Jarvis, R. M., Göttert, J., Murphy, M. P., & Ledgerwood, E. C. (2007). Mitochondria-targeted antioxidants do not prevent tumour necrosis factor-induced necrosis of L929 cells. Free Radical Research, 41(9), 1041-1046.

Westphal, D., Ledgerwood, E. C., Hibma, M. H., Fleming, S. B., Whelan, E. M., & Mercer, A. A. (2007). A novel Bcl-2-like inhibitor of apoptosis is encoded by the parapoxvirus orf virus. Journal of Virology, 81(13), 7178-7188.

Hughes, G., Murphy, M. P., & Ledgerwood, E. C. (2005). Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor κB to modulate tumour necrosis factor-induced apoptosis: Evidence from mitochondria-targeted antioxidants. Biochemical Journal, 389, 83-89.

Smith, R. A. J., Kelso, G. F., Blaikie, F. H., Porteous, C. M., Ledgerwood, E. C., Hughes, G., … Filipovska, A., & Murphy, M. P. (2003). Using mitochondria-targeted molecules to study mitochondrial radical production and its consequences. Biochemical Society Transactions, 31, 1295-1299.

Kelso, G. F., Porteous, C. M., Hughes, G., Ledgerwood, E. C., Gane, A. M., Smith, R. A. J., & Murphy, M. P. (2002). Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants. Annals of the New York Academy of Sciences, 959, 263-274.

Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A. J., & Murphy, M. P. (2001). Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapopotic properties. Journal of Biological Chemistry, 276(7), 4588-4596.

Ledgerwood, E. C., O'Rahilly, S., & Surani, M. A. (2000). The imprinted gene Peg3 is not essential for tumour necrosis factor alpha signaling. Laboratory Investigation, 80(10), 1509-1511.

Scarlett, J. L., Sheard, P. W., Hughes, G., Ledgerwood, E. C., Ku, H.-H., & Murphy, M. P. (2000). Changes in mitochondrial membrane potential during staurosporine-induced apoptosis in Jurkat cells. FEBS Letters, 475, 267-272.

Ledgerwood, E. C., O'Rahilly, S., & Surani, M. A. (2000). The imprinted gene Peg3 is not essential for tumor necrosis factor alpha signaling. Laboratory Investigation, 80, 1509-1511.

Faraco, P. R., Ledgerwood, E. C., Vandenabeele, P., Prins, J. B., & Bradley, J. R. (1999). Tumor necrosis factor induces distinct patterns of caspase activation in WEHI-164 cells associated with apoptosis or necrosis depending on cell cycle stage. Biochemical & Biophysical Research Communications, 261, 385-392.

Jones, S. J., Ledgerwood, E. C., Prins, J. B., Galbraith, J., Johnson, D. R., Pober, J. S., & Bradley, J. S. (1999). TNF recruits TRADD to the plasma membrane but not the trans-Golgi network, the principle subcellular location of TNF-R1. Journal of Immunology, 162, 1042-1048.

Ledgerwood, E. C., Pober, J. S., & Bradley, J. R. (1999). Recent advances in the molecular basis of TNF signal transduction. Laboratory Investigation, 79, 1041-1050.

Faraco, P. R., Ledgerwood, E. C., & Smith, K. G. C. (1998). Apoptosis in renal disease. Sepsis, 2, 31-37.

Ledgerwood, E. C., Prins, J. B., Bright, N. A., Johnson, D. R., Wolfreys, K., Pober, J. S., … Bradley, J. R. (1998). Tumor necrosis factor is delivered to mitochondria where a tumor necrosis factor-binding protein is localized. Laboratory Investigation, 78, 1583-1589.

Prins, J. B., Ledgerwood, E. C., & et al (1998). Tumor necrosis factor-induced cytotoxicity is not related to rates of mitochondiral morphological abnormalities or authophage - chnages trhat can be mediated by TNFR-I or TNFR-II. Bioscience Reports, 18, 329-340.

Min, W., Bradley, J. R., Savidge, J., Jones, S. J., Ledgerwood, E. C., & Pober, J. S. (1998). The N-terminal domains target TRAF2 to the nucleus and display transcriptional regulatory activity. Journal of Immunology, 161, 319-324.

Ledgerwood, E. C., Brennan, S. O., & George, P. M. (1997). Endoproteases other than furin have a role in hepatic proprotein processing. Biochemistry & Molecular Biology International, 42(6), 1131-1142.

Ledgerwood, E. C., Brennan, S. O., Birch, N. P., & George, P. M. (1996). The specificity of the neuroendocrine convertase PC3 is determined by residues NH2-and COOH-terminal to the cleavage site. Biochemistry & Molecular Biology International, 39(6), 1167-1176. doi: 10.1080/15216549600201352

Ledgerwood, E. C., Brennan, S. O., Cawley, N. X., Loh, Y. P., & George, P. M. (1996). Yeast aspartic protease 3 (Yap3) prefers substrates with basic residues in the P2, P1 and P2' positions. FEBS Letters, 383(1-2), 67-71. doi: 10.1016/0014-5793(96)00219-0

Hill, R. M., Ledgerwood, E. C., Brennan, S., Pu, L. P., Loh, Y. P., Christie, D., & Birch, N. P. (1995). Comparison of the molecular forms of the Kex2/subtilisin-like serine proteases SPC2, SPC3, and furin in neuroendocrine secretory vesicles reveals differences in carboxyl-terminus truncation and membrane association. Journal of Neurochemistry, 65, 2318-2326.

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