Role of conformational dynamics in pathogenic protein aggregation |
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| Affiliation: | 1. State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Department of Physics, Fudan University, Shanghai 200438, People''s Republic of China;2. MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi''an Jiaotong University, Xi''an 710049, People''s Republic of China;1. Department of Pharmacy, Wuhan Mental Health Center, Wuhan, China;2. Department of Pharmacy, Wuhan Hospital for Psychotherapy, Wuhan, China;3. Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;4. Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA;5. Department of Pharmacy, The Third Hospital of Wuhan, Tongren Hospital of Wuhan University, Wuhan, China |
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| Abstract: | The accumulation of pathogenic protein oligomers and aggregates is associated with several devastating amyloid diseases. As protein aggregation is a multi-step nucleation-dependent process beginning with unfolding or misfolding of the native state, it is important to understand how innate protein dynamics influence aggregation propensity. Kinetic intermediates composed of heterogeneous ensembles of oligomers are frequently formed on the aggregation pathway. Characterization of the structure and dynamics of these intermediates is critical to the understanding of amyloid diseases since oligomers appear to be the main cytotoxic agents. In this review, we highlight recent biophysical studies of the roles of protein dynamics in driving pathogenic protein aggregation, yielding new mechanistic insights that can be leveraged for design of aggregation inhibitors. |
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| Keywords: | Amyloid disease Oligomeric intermediates Biophysical characterization Transthyretin Abeta Huntingtin Alpha-synuclein Aβ α-synuclein |
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