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Personal profile

Research interests

Our Laboratory studies the structure and function of proteins involved in the fibrinolytic system, memory and neuroplasticity and innate immunity; specifically their roles in human health and diseases.

 

Biography

RL did her PhD on yeast mitochondrial bioenergetics under the supervision of Prof Philip Nagley and Rodney Devenish at Monash University. She then joined the Autogen led by Profs Ian Mackey and Merrill Rowley to investigate the correlation between glutamic acid decarboxylase in the development of Type II diabetes mellitus before working on the role of cathepsin in liver fluke infection then as a project leader in the Molecular Parasitology group led by Prof Terry Spithill. In 2002, she joined the Structural Biology Group led by Prof James Whisstock as a senior scientist and administer within the group. In 2017, she was appointed the group leader in the Department of Biology and Molecular Biology. She enjoys being a hands-on researcher tackling challenging targets and mentoring students to develop their careers within and outside research. 

Currently, RL's research focusses on the structural and functional biology of molecules related to proteases and inhibitors, and molecules related to immunity. Her expertise lies in molecular biology, immunology, protein chemistry, X-ray crystallography, small angle x-ray scattering and electron microscopy. She is passionate to expanse the knowledge gained in the development of therapeutic molecules that aids the management/treatments of diseases.


A few highlights of her research and discovery (in reverse order):

1. Crystallization of human plasminogen: this work was published in Cell Reports (2012); it reveals how circulating plasminogen resists activation until it binds to the fibrin clots or target cell surface. It also explains how pathogens (such as Streptococcus) hijacks this potent plasma protease and during the invasion.

2. Crystallization of perforin: this work was published in Nature (2010), and it reveals how perforin assembles on the surface of the target cell to form transmembrane pores.

3. Crystallization of the first perforin-like (MACPF) protein: this work was published in Science (2007), and it uncovers the molecular structure and mechanism of pore formation by perforin-like proteins. This work revealed the unexpected finding that perforin-like proteins are homologous to bacterial toxin cholesterol-dependent cytolysin (CDC).

4. Crystallization of both human glutamic decarboxylase (GAD) isoforms: this work was published in Nature Structure and Molecular Biology (2007). It provides central insight into the regulatory mechanism by which gamma-aminobutyric acid (GABA, a neurotransmitter inhibitor) production in mammals is through a dynamic catalytic loop and how the two isoforms cooperate to accommodate for the different physiological requirement in the body.

5. Crystallization of serine protease inhibitor proteins: in particular human Maspin and mouse alpha2-antiplasmin: these works were published in Journal of Biological Chemistry and Blood (2005 and 2008, respectively). Maspin was proposed to be a human tumour suppressor that plays a vital role in inhibiting breast cancer migration. Alpha2-antiplasmin is the primary inhibitor of the fibrinolytic protease plasmin. The structural study reveals that the C-terminus of the molecule mediates this inhibitor to inhibit its target protease very efficiently.


6. Liver fluke costs the agricultural industry millions of dollars each year through loss of livestock production, stock deaths, and costs of treatment and prevention. For many years, detection of liver fluke-infected livestock was not possible, especially in developing countries. Cathepsin B is produced by liver flukes and can be found in the faecal material when animals are infected. RL facilitated the development of an expression system to express enzymatically active cathepsin B (2003, Infection and Immunity, first author) and the purified protein was used to develop a diagnostic kit for liver fluke infection in sheep and cattle in South Asia (2009, J Parasitology).


7. During Rl's PhD, she studied the relocation of mitochondrial genes into the nucleus and successfully restored mitochondrial ATP synthase activity with a nuclearly expressed mitochondrial gene (1988, FEBS letts, 1990 EJB, 1990 BBA). This study allowed for the development of strategies to address mutational problems found in diseases caused by mitochondrial gene mutations.

Research area keywords

  • Structure/Function (Health/Safety/Medical)
  • X-ray Crystallography
  • Small Angle X-ray Scattering
  • Electron Microscopy
  • Immunology

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Projects 2001 2020

Research Output 1987 2019

2 Citations (Scopus)

Characterising the Subsite Specificity of Urokinase-Type Plasminogen Activator and Tissue-Type Plasminogen Activator using a Sequence-Defined Peptide Aldehyde Library

Li, C. Y., de Veer, S. J., Law, R. H. P., Whisstock, J. C., Craik, D. J. & Swedberg, J. E., 2 Jan 2019, In : ChemBioChem. 20, 1, p. 46-50 5 p.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
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5 Citations (Scopus)

Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma

Swedberg, J. E., Wu, G., Mahatmanto, T., Durek, T., Caradoc-Davies, T. T., Whisstock, J. C., Law, R. H. P. & Craik, D. J., 2019, In : Journal of Medicinal Chemistry. 62, 2, p. 552-560 9 p.

Research output: Contribution to journalArticleResearchpeer-review

Solution structural model of the complex of the binding regions of human plasminogen with its M-protein receptor from Streptococcus pyogenes

Yuan, Y., Ayinuola, Y. A., Singh, D., Ayinuola, O., Mayfield, J. A., Quek, A., Whisstock, J. C., Law, R. H. P., Lee, S. W., Ploplis, V. A. & Castellino, F. J., 1 Oct 2019, In : Journal of Structural Biology. 208, p. 18-29 12 p.

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Structural studies of plasmin inhibition

Wu, G., Quek, A. J., Caradoc-Davies, T. T., Ekkel, S. M., Mazzitelli, B., Whisstock, J. C. & Law, R. H. P., 5 Mar 2019, In : Biochemical Society Transactions. 47, 2, p. 541-557 17 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding

Quek, A. J. H., Mazzitelli, B. A., Wu, G., Leung, E. W. W., Caradoc-Davies, T. T., Lloyd, G. J., Jeevarajah, D., Conroy, P. J., Sanderson-Smith, M., Yuan, Y., Ayinuola, Y. A., Castellino, F. J., Whisstock, J. C. & Law, R. H. P., 6 Sep 2019, In : Journal of Molecular Biology. 431, 19, p. 3804-3813 10 p.

Research output: Contribution to journalArticleResearchpeer-review