3 April 2014
A new window into the behaviour of ‘molecular chameleon’ proteins could provide the key to developing more-effective drugs for treating diseases such as Parkinson’s.
A molecular chameleon protein doesn’t have a single favoured 3D structure. Instead it has the flexibility to adopt different structures in response to its environment and the proteins and other molecules it encounters. As a result, it can carry out a range of tasks. Molecular chameleons are also known as ‘intrinsically disordered’ or ‘intrinsically unstructured’ proteins. However, sometimes this flexibility can lead to the protein developing a structure that has pathological consequences. How this happens is poorly understood, but understanding it is the key to developing treatments for the so-called protein misfolding diseases, the most common being Alzheimer’s and Parkinson’s.
Melbourne researchers studying the role of a molecular chameleon in Parkinson’s disease are delighted with the results they can get from a new tool: the small angle x-ray scattering (SAXS) beamline at the Australian Synchrotron. They are investigating alpha-synuclein, a protein whose functions are not well-understood but is implicated in the development of the insoluble amyloid fibril aggregates associated with Parkinson’s. Parkinson’s disease is a chronic, progressive, incurable and disabling neurological condition that affects around 64,000 Australians, with more than 80 percent of sufferers being over 65 years of age.
SAXS provides unique information on the shape and size of molecules in solution, showing which particular conformations the molecular chameleon adopts and how these are influenced by a range of factors. The SAXS information complements and extends results gained from laboratory techniques such as nuclear magnetic resonance (NMR), fluorescence resonance energy transfer (FRET) and atomic force microscopy (AFM).
Dr Cyril Curtain, an Honorary Research Fellow at the University of Melbourne Department of Pathology, used SAXS in combination with sophisticated modelling techniques (ensemble optimisation modelling) to investigate alpha-synuclein. His results suggest that one particular conformation, in which the protein is extended rather than compact, may be a key stage in the formation of the damaging fibrils. The fibrils are considered to result from misfolded proteins aggregating together.
“Synchrotron SAXS is exactly what we need to advance our Parkinson’s work,” Cyril said. “Because it offers automated handling of large numbers of samples, we can use it to investigate a lot of different combinations of the factors that might influence the conformations adopted by alpha-synuclein.”
Cyril and his collaborators, including Dr Nigel Kirby who leads the Australian Synchrotron’s SAXS team, are continuing the work with a focus on conformational changes in fibrillisation-prone mutants and the mechanism of action of some known amyloid inhibitors.
“The Synchrotron’s SAXS beamline is a leader on the world stage for measuring extremely weakly scattering samples, a capability often needed when tackling challenging biological systems,” Nigel said. “Researchers can set up their samples for automated data collection at rates as high as 500 samples a day, which helps them systematically investigate whole systems rather than just analysing a few samples. Scientific computing support from NeCTAR (National eResearch Collaboration Tools and Resources) plus the MASSIVE supercomputer allows researchers to work efficiently with the large volumes of data produced by a high performance beamline.”
”Our experiments are unique in that we are able to observe directly changes in protein folding in relation to whether they will be benign or lead to pathological outcomes,” Cyril said. “Preliminary results have shown that it is possible to influence these pathways and our next steps will be to test a number of potential anti-Parkinson drugs as proof of principle.”
Intrinsically disordered proteins are a hot topic in biomedical science. Leading scientific journal Cell recently noted (154, 1 August 2013) that intrinsically disordered proteins “feature in many of the cell’s most productive multitaskers, proteins whose functions are especially fluid, dynamic and diverse”.
Cyril Curtain is an Honorary Research Fellow at the University of Melbourne Department of Pathology, an Adjunct Research Associate at the School of Physics Monash University and a Fellow of the Florey Institute of Neuroscience and Mental Health.