Biochemistry
Laboratory

"The best part of my work
is the discovery. It's seeing
something that nobody has
seen before,"

Dr Tara Christie 

Dr Tara Christie

Head, Biochemistry Laboratory

research overview

Key Research Areas

  • Structural Biology
  • Protein Biochemistry
  • Protein structure-function

Research Overview

Led by Dr Tara Christie, the Biochemistry Laboratory studies the structure and function of proteins - the fundamental molecular engines in all living cells. Understanding the relationship between a protein's structure and its function is essential to discovering the underlying cause of disease and is fundamental to drug design.

 Dr Christie and her team use X-ray crystallography to uncover the atomic structure of proteins, and use a range of biochemical techniques to understand protein function. Her research interests include nucleocytoplasmic transport, mRNA degradation and antibody engineering. Many diseases have been linked to the deregulation of nuclear import and mRNA decay processes. Understanding these pathways will facilitate the development of gene/ drug delivery technologies as well as targeted gene silencing therapeutics for various disorders including cardiovascular disease.

research projects

There are 2 key projects underway in the Biochemistry Laboratory, led by Dr Tara Christie;

1. Regulation of mRNA degradation by nucleocytoplasmic localisation of decay factors

MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression by translational repression and mRNA degradation. miRNAs are central to almost all cellular processes, including cardiovascular development and disease. Our lab investigates the mechanism of miRNA-mediated mRNA degradation, particularly how the nucleocytoplasmic location of mRNA decay factors affects the mRNA decay process.

2. Structural basis of antibody stabilisation

The use of monoclonal antibodies as therapeutic agents has revolutionised the treatment of cancer and many inflammatory diseases. However, many antibodies inherently display poor stability and a tendency to aggregate, particularly when produced at therapeutically relevant quantities, limiting the development of novel antibody therapeutics. In collaboration with Daniel Christ’s laboratory at the Garvan Institute, we are using X-ray crystallography to understand antibody stabilisation to engineer antibodies that are resistant to aggregation and are therapeutically effective.   

laboratory members & Collaborators

Laboratory

Ansha Malik, PhD student (Garvan Institute of Medical Research/ UNSW)

Mahmoud Abdelatti, PhD student (Garvan Institute of Medical Research/ UNSW)

Collaborators

Prof Bostjan Kobe, The University of Queensland

Prof Jade Forwood, Charles Sturt University

A/Prof Daniel Christ, The Garvan Institute of Medical Research

publication highlights

1. Davies, R.B., Smits, C., Wong, A.S.W., Stock, D., Christie, M., Sandin, S., Stewart, A.G. 2017. Cryo-EM analysis of a domain antibody bound rotary ATPase complex. Journal of Structural Biology, 197(3), 350-353  

2. Rouet, R., Langley, D.B., Schofield, P., Christie, M., Roome, B., Porebski, B.T., Buckle, A.M., Clifton, B.E., Jackson, C.J., Stock, D., Christ, D. 2017. Structural reconstruction of protein ancestry. Proceedings of the National Academy of Sciences USA, 114(!5), 3897-3902

3. Christie, M., Chang, C.W., Rona, G., Smith, K.M., Stewart, A.G., Takeda, A.A.S., Fontes, M.R.M., Stewart, M., Vertessy, B.G., Forwood, J.K., Kobe, B. 2016. Structural biology and regulation of protein import into the nucleus. Journal of Molecular Biology, 428 (10): 2060-2090.

4. Allen, M.D., Christie, M., Jones, P., Porebski, B.T., Roome, B., Freund, S.M.V., Buckle, A.M., Bycroft, M., Christ, D. 2015. Solution structure of a soluble fragment derived from a membrane protein by shotgun proteolysis. Protein Engineering Design and Selection, 28(10): 445-450

5. Rouet, R., Dudgeon, K., Christie, M., Langley, D., Christ, D. 2015. Fully human VH single domains that rival the stability and cleft recognition of camelid antibodies. Journal of Biological Chemistry, 290(19): 11905-11917

6. Rona, G., Borsos, M., Ellis, J.J., Mehdi, A., Christie, M., Kornyei, Z., Toth, J., Bozoky, Z., Buday, L., Madarasz, E., Boden, M., Kobe, B., Vertessy, B.G. 2014. Dynamics of re-constitution of the human nuclear proteome after cell division is regulated by NLS-adjacent phosphorylation. Cell Cycle, 13(22): 3551-3564

7. Jonas, S#., Christie, M#., Peter, D., Bhandari, D., Loh, B., Huntzinger, E., Weichenrieder, O., Izaurralde, E. 2014. An asymmetric PAN3 dimer recruits a single PAN2 exonuclease to mediate mRNA deadenylation and decay. Nature Structural and Molecular Biology, 21:599-608 (#Joint first authors)

8. Roman, N#., Christie, M#., Swarbrick, C.M., Kobe, B., Forwood, J.K. 2013. Structural characterization of the nuclear import receptor importin-α in complex with the bipartite NLS of Prp20. PLoS One, 8(12): e82038 (#joint first authors)

9. Christie, M#., Boland, A#., Huntzinger, E., Weichenrieder, O., Izaurralde, E. 2013. Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Molecular Cell, 51(3): 360-373 (#joint first authors)

10. Rona, G., Marfori, M., Borsos, M., Scheer, I., Takacs, E., Toth, J., Magyar, A., Erdei, A., Bozoky, Z., Buday, L., Kobe, B., Vertessy, B.G. 2013. Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights. Acta Crystallographica Section D, 69(12): 2495-2505

11. Marfori, M^., Lonhienne, T., Forwood, J.K., Kobe, B. 2012. Structural characterization of the importin-α:high affinity cNLS interaction. Traffic; 13:532-548

12. Marfori, M., Kobe, B., Forwood, J.K. 2011. Ligand-induced conformational changes within a hexameric Acyl-CoA Thioesterase, Journal of Biological Chemistry; 286(41): 35643-9

13. Marfori, M., Mynott, A., Ellis, J., Mehdi, A., Saunders, N.F.W., Curmi, P.M., Forwood, J.K., Boden, M., Kobe, B. 2011. Molecular basis for specificity of nuclear import and prediction of nuclear localization. Biochimica et Biophysica Acta- Molecular Cell Research, 1813(9): 1562-77

14. Forwood, J.K., Lange, A., Zachariae, U., Marfori, M., Preast. C., Grubmuller, H., Stewart, M., Corbett, A.H., Kobe, B. 2010. Quantitative structural analysis of importin-β flexibility: Paradigm for solenoid protein structures. Structure, 18:1171-1183

15. Lonhienne, T., Forwood, J.K., Marfori, M., Robin, G., Kobe, B., Carroll, B., 2009. Importin-β is a GDP-to-GTP exchange factor of Ran: Implications for the mechanism of nuclear import. Journal of Biological Chemistry, 284(34): 22549-22558

16. Roman, N., Kirkby, B., Marfori, M., Kobe, B., Forwood, J.K., 2009. Crystallisation of the flexible nuclear import receptor importin-β in the unliganded state. Acta Crystallographica Section F, 65(6): 625-628

17. Forwood, J.K., Lonhienne, T., Marfori, M., Robin, G., Meng, W.N., Guncar, G., Liu, S.M., Carroll, B.J. Kobe, B. 2008. Kap95p binding induces the switch loops of RanGDP to adopt the GTP-bound conformation: Implications for nuclear import complex assembly dynamics. Journal of Molecular Biology, 383(4): 772-782

18. Kobe, B., Guncar, G., Buchholz, R., Huber, T., Maco, B., Cowieson, N., Martin, J.L., Marfori, M., Forwood, J.K. 2008, Crystallography and protein-protein interactions: biological interfaces and crystal contacts. Biochemical Society Transactions, 36:1438-1441

19. Forwood, J.K., Thakur, A., Guncar, G., Marfori, M., Mouradov, D., Meng, W.N., Robinson, J., Huber, T., Kellie, S., Martin, J.L., Hume, D.A., Kobe, B. 2007, Structural basis for recruitment of tandem hotdog domains in acyl-CoA thioesterase 7 and its role in inflammation. Proceedings of the National Academy of Sciences USA, 104: 10382-10387 

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