The long-term objective of this research is to develop a detailed, atomic-resolution structural and functional understanding of protein aggregation and fibrillation relevant to human disease, principally with studies of alpha-synuclein. Wild type alpha-synuclein and its mutants (A30P, E46K and A53T) associated with early- onset Parkinson's disease (PD) will be examined in several structural states, including protofibrils, fibrils and membrane-associated complexes. We propose that the chemical details of these structures determine the natural physiological function of alpha-synuclein and, in the mutants and/or under environmental stress, contribute to PD pathology. Moreover, we propose that conversion among several structural states is an essential feature of synucleins;this structural plasticity is likely to be required for neuronal development and maintenance. To examine these structures, magic-angle spinning (MAS) solid-state NMR (SSNMR) experiments will be employed, elucidating details of conformation and dynamics that are inaccessible to other experimental techniques.
Alpha-synuclein is a central player in Parkinson's disease. The precise relationships between alpha-synuclein structure and this disease are not yet well understood. Our proposed studies aim to advance this fundamental knowledge, which will assist the broader research community in developing improved diagnostic tools and therapies for Parkinson's disease.
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|Shi, Xiangyan; Rienstra, Chad M (2016) Site-Specific Internal Motions in GB1 Protein Microcrystals Revealed by 3D ²H-¹³C-¹³C Solid-State NMR Spectroscopy. J Am Chem Soc 138:4105-19|
|Lin, Wayne; Insley, Thomas; Tuttle, Marcus D et al. (2015) Control of protein orientation on gold nanoparticles. J Phys Chem C Nanomater Interfaces 119:21035-21043|
|Courtney, Joseph M; Ye, Qing; Nesbitt, Anna E et al. (2015) Experimental Protein Structure Verification by Scoring with a Single, Unassigned NMR Spectrum. Structure 23:1958-66|
|Rienstra, Chad M (2013) Amyloid structures from Alzheimer's disease patients. Structure 21:1722-3|
|Tang, Ming; Nesbitt, Anna E; Sperling, Lindsay J et al. (2013) Structure of the disulfide bond generating membrane protein DsbB in the lipid bilayer. J Mol Biol 425:1670-82|
|Comellas, Gemma; Rienstra, Chad M (2013) Protein structure determination by magic-angle spinning solid-state NMR, and insights into the formation, structure, and stability of amyloid fibrils. Annu Rev Biophys 42:515-36|
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