A Helical Structural Nucleus Is the Primary Elongating Unit of Insulin Amyloid Fibrils

• DOI: 10.1371/journal.pbio.0050134
• Publication Date: 2007-04-27T13:46:49Z
• Authors: Bente Vestergaard; Minna Groenning; Manfred Roessle; Jette S Kastrup; Marco van de Weert; James M Flink; Sven Frokjaer; Michael Gajhede; Dmitri I Svergun
• Keywords: Oligomer; Fibrillation; Amyloid (mycology)

Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This in part due inherent experimental challenge associated with structural descriptions of individual components dynamic multi-component equilibrium. There indications that oligomeric aggregated precursors fibrillation, and not mature fibrils, main cause cytotoxicity disease. further emphasizes importance characterizing early events. Here we present kinetic x-ray solution scattering study insulin revealing three major components: monomers, an species. Low-resolution three-dimensional structures determined for fibril repeating unit oligomer, latter being helical composed five six monomers. oligomer likely nucleus, which accumulates above supercritical concentration used our experiments. The growth rate fibrils proportional amount solution, suggesting these oligomers elongate fibrils. Hence, nucleus elongating may same component concentrations. A novel elongation pathway proposed, based on shape size precursor. distinct described this defines conceptually new basis structure-based drug design against diseases.