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Professor John Carver
1979: B.Sc. (Hons), University of Adelaide
1983: Ph.D. Australian National University
1983-1985: Post-doctoral Research Fellow, Department of Biochemistry, University of Oxford, UK
1986-1987: Senior Teaching Fellow, Department of Biochemistry, University of Adelaide
1988-1991: Lecturer, Department of Chemistry, University of Wollongong
1992-1996: Senior Lecturer, Department of Chemistry, University of Wollongong
1997-2004: Associate Professor, Department of Chemistry, University of Wollongong
2004-2008: Professor and Head, School of Chemistry & Physics, University of Adelaide
2008-present: Deputy Executive Dean, Faculty of Sciences, University of Adelaide
2009-present: Acting Head, School of Molecular and Biomedical Science, University of Adelaide
Protein Structure, Function and Interactions
Protein chemical, spectroscopic and biophysical methods are used to investigate the structure, function and interactions of various peptides and proteins. Methods include NMR spectroscopy, circular dichroism and fluorescence spectroscopy, electron microscopy and ultracentrifugation techniques. Site directed mutagenesis is used to investigate structure-function relationships of specific amino acids within these proteins.
In a major program of research, the structure and mechanism of action of small heat-shock proteins (sHsps) are being studied. In vivo, sHsps function as molecular chaperones to stabilise proteins under conditions of cellular stress (e.g. heat, heavy metals, infection and inflammation) and their over-expression is associated with a broad range of diseases (e.g. cataract, neurological diseases and some cancers). Amyloid fibril formation is a characteristic of diseases associated with protein misfolding and precipitation, e.g. Alzheimer’s, Parkinson’s, Huntington’s and Creutzfeldt-Jakob diseases along with other. As part of these studies, therefore, we are investigating the interaction of fibril-forming peptides and proteins with sHsps. The predominant eye lens protein, alpha-crystallin, is a sHsp and is the major focus of our investigations. Alpha-crystallin has an important role in preventing cataract, a disease that is characterised by aggregation and precipitation of the constituent lens crystallin proteins. The overall goal of our research is to understand the role of sHsps in protein precipitation diseases and thereby potentially develop novel therapeutics.
In a similar manner, the structure and interactions of other chaperone proteins are being examined. For example, we are also investigating the chaperone action of milk casein proteins, particularly with respect to their interaction with other milk proteins and components. The research has potential for the use of caseins in stabilising protein components in foods. We have also discovered that two of the casein proteins are highly prone to form amyloid fibrils with the aggregation of kappa-casein being a very useful model for studying generic aspects of fibril formation.
1. D.T. Humphreys, J.A. Carver, S.B. Easterbrook-Smith and M.R. Wilson. Clusterin has chaperone-like activity similar to that of small heat-shock proteins. J. Biol. Chem. 274, 6875-6881 (1999).
2. D.M. Hatters, R.A. Lindner, J.A. Carver and G.J. Howlett. The molecular chaperone, a-crystallin, inhibits amyloid formation by apolipoprotein C-II. J. Biol. Chem. 276, 33755-33761 (2001).
3. J.A. Carver, R.A. Lindner, C. Lyon, D. Canet, H. Hernandez, C.M. Dobson and C. Redfield. The interaction of the molecular chaperone a-crystallin with unfolding a-lactalbumin: a structural and kinetic spectroscopic study. J. Mol. Biol. 318, 812-827 (2002).
4. S. Meehan, Y. Berry, B. Luisi, C.M. Dobson, J.A. Carver and C.E. MacPhee. Amyloid fibril formation by lens crystallin proteins and its implications for cataract formation. J. Biol. Chem. 279, 3413-3419 (2004).
5. A. Rekas, C.G. Adda, J.A. Aquilina, K.J. Barnham, M. Sunde, D. Galatis, N.A. Williamson, R.F. Anders, C.V. Robinson, R. Cappai and J.A. Carver. Interaction of the molecular chaperone aB-crystallin with a-synuclein: effects on amyloid fibril formation and chaperone activity. J. Mol. Biol. 340, 1167-1183 (2004).
6. D.C. Thorn, S. Meehan, M. Sunde, A. Rekas, S.L. Gras, C.E. MacPhee, C.M. Dobson, M.R. Wilson and J.A. Carver. Amyloid fibril formation by bovine milk k-casein and its inhibition by the molecular chaperones as- and b-casein. Biochemistry 44, 17027-17036 (2005).
7. H. Ecroyd, S. Meehan, J. Horwitz, J.A. Aquilina, J.L.P. Benesch, C.V. Robinson, C.E. MacPhee and J.A. Carver. Mimicking phosphorylation of aB-crystallin affects its chaperone activity. Biochem. J. 401, 129-141 (2007).
8. S. Meehan, T.P. Knowles, A.J. Baldwin, J.F. Smith, A.M. Squires, P. Clements, T.M. Treweek, H. Ecroyd, G.G. Tartaglia, M. Vendruscolo, C.E. MacPhee, C.M. Dobson and J.A. Carver. Characterisation of amyloid fibril formation by small heat-shock chaperone proteins human aA-, aB- and R120G aB-crystallins. J. Mol. Biol. 372, 470-484 (2007).
9. D.C. Thorn, H. Ecroyd, M. Sunde, S. Poon and J.A. Carver. Amyloid fibril formation by bovine milk aS2-casein occurs under physiological conditions yet is prevented by its natural counterpart, aS1-casein. Biochemistry 47, 3926-3936 (2008).
10. H. Ecroyd, T. Koudelka, D.C. Thorn, G. Devlin, D. Williams, P. Hoffmann and J.A. Carver. Dissociation from the oligomeric state is the rate-determing step in amyloid fibril formation by k-casein. J. Biol. Chem. 283, 9012-9022 (2008).
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