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Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

ABSTRACT: Human islet amyloid polypeptide (hIAPP) is a cytotoxic protein that aggregates into oligomers and fibrils that kill pancreatic ?-cells. Here we analyze hIAPP aggregation in vitro, measured via thioflavin-T fluorescence. We use mass-action kinetics and scaling analysis to reconstruct the aggregation pathway, and find that the initiation step requires four hIAPP monomers. After this step, monomers join the nucleus in pairs, until the first stable nucleus (of size approximately 20 monomers) is formed. This nucleus then elongates by successive addition of single monomers. We find that the best-fit of our data is achieved when we include a secondary fibril-dependent nucleation pathway in the reaction scheme. We predict how interventions that change rates of fibril elongation or nucleation rates affect the accumulation of potentially cytotoxic oligomer species. Our results demonstrate the power of scaling analysis in reverse engineering biochemical aggregation pathways.

SUBMITTER: Bailey J

PROVIDER: S-EPMC3396588 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

Bailey J J Potter K J KJ Verchere C B CB Edelstein-Keshet L L Coombs D D

Physical biology 20111125 6

Human islet amyloid polypeptide (hIAPP) is a cytotoxic protein that aggregates into oligomers and fibrils that kill pancreatic β-cells. Here we analyze hIAPP aggregation in vitro, measured via thioflavin-T fluorescence. We use mass-action kinetics and scaling analysis to reconstruct the aggregation pathway, and find that the initiation step requires four hIAPP monomers. After this step, monomers join the nucleus in pairs, until the first stable nucleus (of size approximately 20 monomers) is form ...[more]

PMID: 22120172

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Dataset Information

Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

Publications

Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

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