Stepwise Organization of the {beta}-Structure Identifies Key Regions Essential for the Propagation and Cytotoxicity of Insulin Amyloid Fibrils [Protein Structure and Folding]

February 25th, 2014 by Chatani, E., Imamura, H., Yamamoto, N., Kato, M.

Amyloid fibrils are supramolecular assemblies, the deposition of which is associated with many serious diseases including Alzheimer's, prion, and Huntington's diseases. Several smaller aggregates such as oligomers and protofibrils have been proposed to play a role in the early stages of the fibrillation process; however, little is known about how these species contribute to the formation of mature amyloid fibrils with a rigid cross-β structure. Here, we identified a new pathway for the formation of insulin amyloid fibrils at a high concentration of salt in which mature fibrils were formed in a stepwise manner via a prefibrillar intermediate: minute prefibrillar species initially accumulated, followed by the subsequent formation of thicker amyloid fibrils. FTIR spectra suggested the sequential formation of two types of β-sheets with different strength hydrogen bonds, one of which developed concomitantly with the mutual assembly of the prefibrillar intermediate to form mature fibrils. Interestingly, fibril propagation and cellular cytotoxicity appeared only after the later step of structural organization, and a comparison of β-sheet regions between the prefibrillar intermediate and mature fibrils using proteolysis led to the proposal of specific regions essential for the manifestation of these properties.
  • Posted in Journal of Biological Chemistry, Publications
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