Role of different regions of ?-synuclein in the assembly of fibrils

Document Type

Article

Publication Date

11-20-2007

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 ?-synuclein fibrillation remains elusive. In this study, we used trypsin and endoproteinase GluC to digest intact ?-synuclein fibrils and to analyze the detailed morphology of the resultant fibrils/remnants. We also created three mutants of ?-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 ?-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 ?-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. © 2007 American Chemical Society.

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