SEMINAR

The prevention of protein unfolding and aggregation via molecular chaperone action

Abstract
In vivo, protein aggregation and precipitation are often the consequences of the unfolding or incorrect folding of proteins. These processes have been categorised by the term ‘protein misfolding’. A diversity of diseases, many of them age-related, result from protein misfolding including cataract, Alzheimer’s, Parkinson’s and Huntington’s diseases and haemodialysis-related amyloidosis. Different proteins are associated with each of these diseases. There are a variety of cellular mechanisms that minimise protein aggregation. Arguably, the most important of these is the expression of molecular chaperone proteins which interact with partially folded proteins to prevent their aggregation. Of primary importance in this role is the small heat-shock protein (sHsp) family (Walther et al., 2015).

In this talk, some of our recent work investigating the structure and function of molecular chaperone proteins, particularly sHsps, and their interactions with unfolding and aggregating proteins, will be described. The research involves the use of a variety of biophysical, spectroscopic, protein chemical and cell biological techniques, e.g. NMR, circular dichroism and fluorescence spectroscopy, mass spectrometry, dynamic light scattering and electron microscopy, and provides insights into the mechanism of chaperone action in addition to potential avenues for the application of molecular chaperones in the treatment of protein misfolding diseases.

References
Walther, D.M. et al. (2015) Cell 161, 919-932.

BIOGRAPHY

2013 - present: Director, Research School of Chemistry, Australian National University
2009: Head, School of Molecular and Biomedical Science, University of Adelaide
2008 - 2009: Deputy Executive Dean, Faculty of Sciences, University of Adelaide
2004 - 2008: Head, School of Chemistry & Physics, University of Adelaide
2004 - 2013: Professor of Chemistry, School of Chemistry & Physics, University of Adelaide
1997 - 2004: Associate Professor, Department of Chemistry, University of Wollongong
1992 - 1996: Senior Lecturer, Department of Chemistry, University of Wollongong
1988 - 1991: Lecturer, Department of Chemistry, University of Wollongong
1986 - 1987: Senior Teaching Fellow, Department of Biochemistry, University of Adelaide
1983 - 1985: Post-doctoral Research Fellow, Department of Biochemistry, University of Oxford
1982 - 1983: Research Assistant, Department of Chemistry, Australian National University
1983: Ph.D. in Chemistry, Australian National University
1979: B.Sc. First Class Honours in Physical and Inorganic Chemistry, University of Adelaide

John Carver’s research interests are in protein structure, function and interactions. He investigates the fundamental aspects of protein unfolding and aggregation and the mechanisms by which molecular chaperone proteins prevent protein aggregation. The work has direct relevance to the many diseases of protein aggregation such as Alzheimer’s, Parkinson’s and cataract. Many of these diseases are age-related. He utilises a diversity of spectroscopic, biophysical and protein chemical techniques for his research. He has co-authored over 160 research publications and has received a variety of fellowships.

Recent relevant publications
T.M. Treweek, S. Meehan, H. Ecroyd and J.A. Carver. Small heat-shock proteins: important players in regulating cellular proteostasis. Cell Mol. Life Sci. 72, 429-451 (2015).

D. Cox, J.A. Carver and H. Ecroyd. Preventing -synuclein aggregation: the role of the small heat-shock molecular chaperone proteins. Biochim. Biophys. Acta - Molec. Basis Disease 1842, 1830-1843 (2014).

G.K.A. Hochberg, H. Ecroyd, C. Liu, D. Cox, D. Cascio, M.R. Sawaya, M.P. Collier, J. Stroud, J.A. Carver, A.J. Baldwin, C.V. Robinson, D. Eisenberg, J.L.P. Benesch and A. Laganowsky. A structured core domain of B-crystallin can prevent amyloid fibrillation and associated toxicity. Proc. Natl. Acad. Sci. USA 111, E1562-1570 (2014).

C. Holt, J.A. Carver, H. Ecroyd and D.C. Thorn. Caseins and the casein micelle: their biological functions, structures and behavior in foods. J. Dairy Sci. 96, 6127-6146 (2013).

G. Esposito, M. Garvey, V. Alverdi, F. Pettirossi, A. Corazza, F. Fogolari, M. Polano, P.P. Mangione, S. Giorgetti, M. Stoppini, A. Rekas, V. Bellotti, A.J.R. Heck and J.A. Carver. Monitoring the interaction between 2-microglobulin and the molecular chaperone B-crystallin by NMR and mass spectrometry. B-Crystallin dissociates 2-microglobulin oligomers. J. Biol. Chem. 288, 17844-17858 (2013).