Head of Laboratory

On this page:

Overview

We use biophysical and biochemical techniques to study the structure and formation of amyloid fibrils, in particular functional amyloid deposits. We have determined the solution structures of several fungal hydrophobin proteins that form functional amyloid coatings on fungal spores and which mediate the interaction between fungus and host during infection. We have used mutagenesis to identify key regions of the hydrophobins that drive intermolecular association. This is allowing us to propose methods of inhibiting amyloid formation and also of engineering hydrophobins with new properties. Hydrophobins are unusual in that they form amphipathic amyloid monolayers and we are able to produce hydrophobins that display novel functionalities on either the hydrophilic or the hydrophobic face of the monolayer. These engineered amyloid coatings are being used to functionalise nanomaterials.

Research achievements

Before the 1990’s, the deposition of insoluble protein aggregates had been noted in many diseases, including Alzheimer’s, prion diseases and type II diabetes but the underlying mechanism of amyloid formation was unknown. During my early postdoctoral studies in the UK with Colin Blake, I carried out some of the first X ray fibre diffraction and electron microscopy studies of amyloid fibrils. I used these to examine the molecular structure of amyloid fibrils and was able to demonstrate for the first time that all amyloid fibrils, regardless of the nature of the component protein or disease involved, have the same core β sheet structure (J. Mol. Biol. (1997) 273, 729-39). I additionally solved the three-dimensional structures of two amyloidogenic human lysozyme variants and carried out other biophysical studies on these proteins that investigated the molecular basis for their transformation into insoluble aggregates. This was the first demonstration that protein misfolding underlies amyloid formation (Nature (1997) 385, 787-93).

The Sunde Group at the University of Sydney is now focussed on functional amyloid. Increasingly, research is discovering that Nature uses the stable, self-assembling amyloid structure for functional purposes. In particular we are working on fungal proteins called hydrophobins. These remarkable proteins form amyloid monolayers that coat and protect aerial structures such as spores. The hydrophobin amyloid layers mediate interactions with host surfaces such as cells, during fungal infections of animals and plants. The study of natural amyloids can shed light on the processes that drive the formation of amyloid in disease and in particular may help with the design of inhibitors of the process. This work was the subject of an ARC Discovery Project (DP0879121). We have demonstrated that the process of hydrophobin self-assembly is controlled by surface tension, which may open the way for inhibitors of the process to be developed (Morris et al., 2011). In addition, hydrophobin assemblies are protein-based, can self-assemble, are stable and are also amphipathic. This makes them excellent candidates for coating hydrophobic nanomaterials such as carbon nanotubes and graphene and rendering them more water-soluble and biocompatible. This aspect of our research is the subject of a Discovery Grant we currently hold (DP1093949) and has also been supported by a Linkage Grant with the New Zealand Institute for Crop and Food Research (LP0776672). I have also held a France Australia Science and Technology (FAST) Collaboration Grant with Prof Jean-Paul Latgé of the Pasteur Institute in Paris, to support our efforts on hydrophobins from the human pathogen Aspergillus fumigatus (FAST). We have just started to work on the hydrophobins from Magnaporthe grisea, the fungus that causes rice blast and is responsible for significant rice crop losses worldwide (DP130102957).

Our recent work on hydrophobins has been published in Proc. Natl. Acad. Sci USA (109, E804-11 and 109, 6951-6) and has been presented at the Australian Protein Misfolding and Neurodegeneration Conference (Port Douglas, 2009), the 4th Alzheimer’s and Parkinson’s Disease Symposium (Sydney, 2010) and COMBIO 2011 (Cairns, 2011). My students have received recognition for their high quality work and the interest of their projects. Ingrid Macindoe was a finalist for the Thompson Prize, awarded by the Sydney Protein group (November 2009). Most recently, Vanessa Morris won a travel award and poster prize at the Lorne Proteins Meeting (February 2012) Qin (Jane) Ren was an to give a talk at the XXVth International Conference on Magnetic Resonance in Biological Systems (Lyon 2012).

Major funding sources

Australian Research Council

Major collaborations

Ann Kwan (School of Molecular Bioscience, University of Sydney)
Jean-Paul Latge and Inaki Guijarro (Pasteur Institute)
Alfonso de Simone (University College London)
Rasmus Linser (University of NSW)
Wenrong Yang (Deakin University)

Research project opportunities

Protein self-assembly in nature and disease