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Determination of molecular dynamics in membrane proteins and protein fibrils using novel solid-state NMR methods

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Protein gatherings give way to advancing research

Leaps are being made in the abilities of imaging tools to render information about an organism's biological processes. This is especially effective for following the development of disease.


The 'Determination of molecular dynamics in membrane proteins and protein fibrils using novel solid-state NMR methods' (Dynamic proteins) project investigated the role of alpha-synuclein (AS) in the second most common neurodegenerative disease, Parkinson's (PD). With the help of novel solid-state nuclear magnetic resonance (NMR) methods, researchers set out to examine the molecular dynamics of membrane proteins and protein fibrils. The goal was to understand how fibril proteins aggregate at the molecular level and to reveal the various stages by which they assemble (known as the fibrilisation process) into clumps of insoluble proteinaceous deposits (termed amyloid fibrils). In the case of the brains of PD patients, these deposits are composed of fibrillar aggregates rich in beta sheets. A beta sheet is a secondary structure in proteins made up of beta strands, which are stretches of polypeptide chains. The fibrillar aggregates are mainly made up of AS, so it is critical to uncover the role this protein plays in the cause of PD. A higher level of beta sheets has been implicated in many human diseases. Dynamic proteins applied two-dimensional solid-state NMR to reveal the structure of alpha-fibrils at an atomic level. Resulting data helped to determine the organisation of beta strands and show that the core region of AS does not have very mobile bulk water, hence the insoluble character. Increasing evidence suggests that the prefibrillar intermediates are the primary causative agents in neurodegeneration. Using biophysical techniques, electrophysiological measurements and solid-state NMR, Dynamic proteins was able to study AS oligomers (protein complexes) and how they form into fibrils. The project's results have contributed to a better understanding of fibril organisation and the structural preferences of oligomers. These findings can facilitate further studies of the structural biology of various states of AS, which can then be applied for enhanced drug development.

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