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Protein Folding, Misfolding and Aggregation

One of the major advantages of mass spectrometry (MS) and ion mobility-mass spectrometry (IM-MS) is the ability to measure one species in the presence of many others. This feature is already widely utilized for the analysis of complex mixtures in proteomics and metabolomics and has recently been shown to be also of exceptional use for structural biology. Instead of adopting one defined oligomerization state, some proteins exist as equilibrium of several distinctly sized species. These so-called polydisperse assemblies cannot be analyzed directly by conventional solution-phase methods, which exclusively yield data that reflect the average of the entire ensemble. With MS and IM-MS on the other hand, specific non-covalently associated oligomers can be probed directly out of their heterogeneous in vitro environment without changing the underlying equilibrium.

The most relevant example of polydisperse systems are probably amyloid forming proteins occurring in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These proteins undergo a spontaneous transition from a soluble, often partially folded form into an insoluble, beta-sheet rich amyloid fibril. The underlying assembly pathway is not fully understood to date, but there has been increasing evidence that oligomeric folding intermediates, which occur during the transformation process, are the toxic species in the above-mentioned diseases. Their structure however, is far from being understood. Here we aim to characterize pre-selected oligomers of polydisperse protein assemblies regarding their secondary, tertiary, and quaternary structure using a combination of MS, IM-MS and gas-phase spectroscopy techniques.

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