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Department of Biochemistry profile

Associate Professor Liz Ledgerwood

PositionAssociate Professor
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

Dunstan-Harrison, C., Morison, I. M., & Ledgerwood, E. C. (2021). A novel frameshift GP1BB mutation causes autosomal dominant macrothrombocytopenia with decreased vWF receptor expression but normal platelet aggregation. Platelets. Advance online publication. doi: 10.1080/09537104.2021.1909716

Das, A., Middleton, A. J., Padala, P., Ledgerwood, E. C., Mace, P. D., & Day, C. L. (2021). The structure and ubiquitin binding properties of TRAF RING heterodimers. Journal of Molecular Biology. Advance online publication. doi: 10.1016/j.jmb.2021.166844

Fellner, M., Parakra, R., McDonald, K. O., Kass, I., Jameson, G. N. L., Willbanks, S. M., & Ledgerwood, E. C. (2021). Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity. Biochemical Journal, 478(3), 669-684. doi: 10.1042/bcj20200793

Ledgerwood, E. C., Dunstan-Harrison, C., Ong, L., & Morison, I. M. (2019). CYCS gene variants associated with thrombocytopenia. Platelets, 30(5), 672-674. doi: 10.1080/09537104.2018.1543866

Parakra, R. D., Kleffmann, T., Jameson, G. N. L., & Ledgerwood, E. C. (2018). The proportion of Met80-sulfoxide dictates peroxidase activity of human cytochrome c. Dalton Transactions, 47, 9128. doi: 10.1039/c8dt02185f

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.

Chapter in Book - Research

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

Chapter in Book - Research

Das, A., Middleton, A. J., Padala, P., Ledgerwood, E. C., Mace, P. D., & Day, C. L. (2021). The structure and ubiquitin binding properties of TRAF RING heterodimers. Journal of Molecular Biology. Advance online publication. doi: 10.1016/j.jmb.2021.166844

Journal - Research Article

Fellner, M., Parakra, R., McDonald, K. O., Kass, I., Jameson, G. N. L., Willbanks, S. M., & Ledgerwood, E. C. (2021). Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity. Biochemical Journal, 478(3), 669-684. doi: 10.1042/bcj20200793

Journal - Research Article

Parakra, R. D., Kleffmann, T., Jameson, G. N. L., & Ledgerwood, E. C. (2018). The proportion of Met80-sulfoxide dictates peroxidase activity of human cytochrome c. Dalton Transactions, 47, 9128. doi: 10.1039/c8dt02185f

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

Journal - Research Article

Ong, L., McDonald, K. O., & Ledgerwood, E. C. (2017). Differentiation and cell density upregulate cytochrome c levels in megakaryoblastic cell lines: Implications for analysis of CYCS-associated thrombocytopenia. PLoS ONE, 12(12), e0190433. doi: 10.1371/journal.pone.0190433

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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.

Journal - Research Article

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

Journal - Research Article

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

Journal - Research Article

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.

Journal - Research Article

Dunstan-Harrison, C., Morison, I. M., & Ledgerwood, E. C. (2021). A novel frameshift GP1BB mutation causes autosomal dominant macrothrombocytopenia with decreased vWF receptor expression but normal platelet aggregation. Platelets. Advance online publication. doi: 10.1080/09537104.2021.1909716

Journal - Research Other

Ledgerwood, E. C., Dunstan-Harrison, C., Ong, L., & Morison, I. M. (2019). CYCS gene variants associated with thrombocytopenia. Platelets, 30(5), 672-674. doi: 10.1080/09537104.2018.1543866

Journal - Research Other

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