A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.

Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equi...

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Main Authors: Bente Vestergaard, Minna Groenning, Manfred Roessle, Jette S Kastrup, Marco van de Weert, James M Flink, Sven Frokjaer, Michael Gajhede, Dmitri I Svergun
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2007-05-01
Series:PLoS Biology
Online Access:https://doi.org/10.1371/journal.pbio.0050134
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spelling doaj-89b0e02fe477418e86bcc845bb0617d82021-07-02T21:12:58ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852007-05-0155e13410.1371/journal.pbio.0050134A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.Bente VestergaardMinna GroenningManfred RoessleJette S KastrupMarco van de WeertJames M FlinkSven FrokjaerMichael GajhedeDmitri I SvergunAlthough amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are indications that oligomeric aggregated precursors of fibrillation, and not mature fibrils, are the main cause of cytotoxicity in amyloid disease. This further emphasizes the importance of characterizing early fibrillation events. Here we present a kinetic x-ray solution scattering study of insulin fibrillation, revealing three major components: insulin monomers, mature fibrils, and an oligomeric species. Low-resolution three-dimensional structures are determined for the fibril repeating unit and for the oligomer, the latter being a helical unit composed of five to six insulin monomers. This helical oligomer is likely to be a structural nucleus, which accumulates above the supercritical concentration used in our experiments. The growth rate of the fibrils is proportional to the amount of the helical oligomer present in solution, suggesting that these oligomers elongate the fibrils. Hence, the structural nucleus and elongating unit in insulin amyloid fibrillation may be the same structural component above supercritical concentrations. A novel elongation pathway of insulin amyloid fibrils is proposed, based on the shape and size of the fibrillation precursor. The distinct helical oligomer described in this study defines a conceptually new basis of structure-based drug design against amyloid diseases.https://doi.org/10.1371/journal.pbio.0050134
collection DOAJ
language English
format Article
sources DOAJ
author Bente Vestergaard
Minna Groenning
Manfred Roessle
Jette S Kastrup
Marco van de Weert
James M Flink
Sven Frokjaer
Michael Gajhede
Dmitri I Svergun
spellingShingle Bente Vestergaard
Minna Groenning
Manfred Roessle
Jette S Kastrup
Marco van de Weert
James M Flink
Sven Frokjaer
Michael Gajhede
Dmitri I Svergun
A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
PLoS Biology
author_facet Bente Vestergaard
Minna Groenning
Manfred Roessle
Jette S Kastrup
Marco van de Weert
James M Flink
Sven Frokjaer
Michael Gajhede
Dmitri I Svergun
author_sort Bente Vestergaard
title A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
title_short A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
title_full A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
title_fullStr A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
title_full_unstemmed A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
title_sort helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
publisher Public Library of Science (PLoS)
series PLoS Biology
issn 1544-9173
1545-7885
publishDate 2007-05-01
description Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are indications that oligomeric aggregated precursors of fibrillation, and not mature fibrils, are the main cause of cytotoxicity in amyloid disease. This further emphasizes the importance of characterizing early fibrillation events. Here we present a kinetic x-ray solution scattering study of insulin fibrillation, revealing three major components: insulin monomers, mature fibrils, and an oligomeric species. Low-resolution three-dimensional structures are determined for the fibril repeating unit and for the oligomer, the latter being a helical unit composed of five to six insulin monomers. This helical oligomer is likely to be a structural nucleus, which accumulates above the supercritical concentration used in our experiments. The growth rate of the fibrils is proportional to the amount of the helical oligomer present in solution, suggesting that these oligomers elongate the fibrils. Hence, the structural nucleus and elongating unit in insulin amyloid fibrillation may be the same structural component above supercritical concentrations. A novel elongation pathway of insulin amyloid fibrils is proposed, based on the shape and size of the fibrillation precursor. The distinct helical oligomer described in this study defines a conceptually new basis of structure-based drug design against amyloid diseases.
url https://doi.org/10.1371/journal.pbio.0050134
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