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Professor Philip J Hogg*
Centre for Vascular Research
University of New South Wales
Sydney, NSW 2052
Email: p.hogg@unsw.edu.au
Tel: +61-2-9385-1004
Fax: +61-2-9385-1389
Homepage: http://www.cvr.net.au/research/disulfide.htm
| Research |
Proteins that work outside cells nearly always contain disulphide-bonds, which are covalent links between pairs of cysteine amino acids. The prevailing view is that these bonds have been added during evolution to help hold proteins together, but are otherwise inert. Prof. Hogg and his team have shown that that certain disulphide-bonds have been added to proteins to control how they work, rather than just helping hold the protein together. That is, disulphide-bonds can act as switches for protein function by breaking or forming in a precise way. Two proteins that are controlled in this way are the serine protease plasmin and the cell-surface receptor tissue factor.
Plasmin functions in clot lysis and cell migration. The enzyme contains five consecutive triple disulphide-linked domains (called kringle domains) followed by a serine protease module. An internal fragment of plasmin, called angiostatin, is an inhibitor of tumour blood vessel formation (angiogenesis) and tumour growth. Prof. Hogg’s team has shown that the triggering event for angiostatin formation is hydrolysis of two disulphide-bonds in the 5th kringle domain of plasmin.
Tissue factor initiates coagulation by binding factor VII, which then cleaves factors IX and X. The receptor exists on the cell surface in a cryptic configuration, which rapidly transforms into an active configuration in response to certain stimuli. Prof. Hogg’s team have suggested that the disulfide-bond in the membrane-proximal domain is reduced in the cryptic form of tissue factor and activation involves formation of the disulfide, changing the conformation of nearby sheet residues and allowing productive binding of factors IX and X.
Current research aims at elucidating the molecular mechanisms of cleavage of the plasmin disulphide-bonds and formation of the tissue factor bond and the role that this chemistry plays in the biology of these proteins. |
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| Collaborations |
Prof. Michael Berndt, Monash University
Prof. Deane Mosher, University of Wisconsin, USA
Prof. Chris Parish, John Curtin School of Medical Research
Prof. Francis Castellino, University of Notre Dame, USA
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| Publications |
Stathakis, P., Matthias, L.J., Fitzgerald, M., Chesterman, C.N. and Hogg, P.J. (1997) Generation of angiostatin by reduction and proteolysis of plasmin: catalysis by a plasmin reductase secreted by cultured cells. Journal of Biological Chemistry 272, 20641-20645.
Stathakis, P., Lay, A.J., Fitzgerald, M., Schlieker, C., Matthias, L.J. and Hogg, P.J. (1999) Angiostatin formation involves disulphide bond reduction and proteolysis in kringle 5 of plasmin. Journal of Biological Chemistry 274, 8910-8916.
Lay, A.J., Jiang, X.-M., Kisker, O., Flynn, E., Underwood, A., Condron, R. and Hogg, P.J. (2000) Phosphoglycerate kinase acts in tumor angiogenesis as a disulphide reductase. Nature 408, 869-873.
Lay, A.J., Jiang, X.-M., Daly, E., Sun, L. and Hogg, P.J. (2002) Plasmin reduction by phosphoglycerate kinase is a thiol-independent process. Journal of Biological Chemistry 277, 9062-9068.
Hogg, P.J. (2003) Disulphide-bonds as switches for protein function. Trends in Biochemical Sciences 28, 210-214.
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