Researchers at the University of Pennsylvania have developed a technology similar to that used in tv and film to be able to track the way that proteins fold and change shape. Instead of a person wearing a tracking suit covered in small colored balls being tracked by a cameraman, the protein is labeled with multiple probes at different positions. The study was published in Biophysical Journal.
One of the big fundamental questions in biochemistry is how proteins fold into a certain shape. This is dictated by the sequence of amino acids in the protein, and the interactions of the amino acid side chains.
Professor E. James Petersson, Associate Professor of Chemistry - University of Pennsylvania
The movement of the labeled protein is tracked via fluorescence from the probes, using a technique called fluorescence resonance energy transfer. Scientists measure the multiple distances between different points on the protein similar to motion-capture technology, which gives information on its shape information to understand its shape. The team at the University of Pennsylvania made roughly 30 measurements of differing distances within the protein alpha-synuclein under different states where it's changing shape. The data from the probe positions is used to construct computational models of the structure all the way down to atomic detail.
In healthy bodies, protein shapes contribute to everyday functions, such as transporting oxygen in the blood, but with some diseases, it is thought that a misshapen protein could be the cause. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, proteins misfolding causes them to aggregate into long fibrils, which are toxic to neurons. The new research could lead to drugs that can be used to treat neurodegenerative diseases, as well as improved imaging to allow earlier detection.
Students Jack Ferrie and Jimin Yoon made a series of experimental measurements that were used to direct protein folding, to be consistent with the experimental measurements and allowing them to model protein shapes. With the new approach, the researchers wanted to show that the structures coming out of the computational models were consistent with reality. They carried out three types of experiments to match real data with the models, and the published paper has one of the largest libraries of proteins labeled with synthetic fluorophores that has ever been reported.
The team is now working to apply the new technique to model protein structures in aggregated forms that cause diseases. They want to be able to model responses to drugs that would cause the aggregated proteins to change shape. There have breakthroughs in solving the structures of proteins in neurodegenerative diseases, but also the fluorescence technique allows analysis in living cells.
The ability to watch a protein as it changes shape, and to actually get structures out of that, is a really important basic science goal that we've been working towards for 10 years.
Professor E. James Petersson, Associate Professor of Chemistry - University of Pennsylvania
The team wants to generate model structures that actually show what is the effect of these drugs, by taking the protein with the fluorescent labels, adding the drug, allowing the protein to change shape, making fluorescence measurements and using this in computational modeling to see the structural effect of these drugs.
Petersson explains that there are some promising drugs for treating neurodegenerative diseases that could block this formation of aggregates. “By the time people show cognitive or motor-tremor symptoms, it's too late to use these drugs because there's already too much neurodegeneration, ” mentions Professor Peterson. The probes are a great step forward in neurogenerative research, as they can detect aggregates on the brain, even if patients show no sign of behavioral changes or learning deficits, through non-invasive imaging of the aggregates.
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