Role of Different Regions of α-Synuclein in the Assembly of Fibrils

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Abstract
Elucidating the details of the assembly of amyloid fibrils is a key step to understanding the mechanism of amyloid deposition diseases including Parkinson's disease. Although several models have been proposed, based on analyses of polypeptides and short peptides, a detailed understanding of the structure and mechanism of α-synuclein fibrillation remains elusive. In this study, we used trypsin and endoproteinase GluC to digest intact α-synuclein fibrils and to analyze the detailed morphology of the resultant fibrils/remnants. We also created three mutants of α-synuclein, in which the N-terminal and C-terminal regions were removed, both individually and in combination, and investigated the detailed morphology of the fibrils from these mutants. Our results indicate that the assembly of mature α-synuclein fibrils is hierarchical: protofilaments → protofibrils → mature fibrils. There is a core region of ∼70 amino acids, from residues ∼32 to 102, which comprises the β-rich core of the protofilaments and fibrils. In contrast, the two terminal regions show no evidence of participating in the assembly of the protofilament core but play a key role in the interactions between the protofilaments, which is necessary for the fibril maturation.

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