Journal
ACS CHEMICAL NEUROSCIENCE
Volume 8, Issue 10, Pages 2152-2158Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00251
Keywords
Amyloid; autocatalysis; Finke-Watzky model; growth; kinetics; nucleation; S100A9
Funding
- ALF Vasterbotten Lans Landsting [ALFVLL-369861]
- Swedish Medical Research Council [2014-3241]
- FP-7 Marie Curie Action Nano-Guard [269138]
- Insamlingsstiftelsen [FS 2.1.12-1605-14]
- Biochemical Imaging Platform, Umea University
- FP-7 Marie Curie Career Integration Grant [293476]
- Erasmus+ program
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Quantitative kinetic analysis is critical for understanding amyloid mechanisms. Here we demonstrate the application of generic Finke-Watzky (F-W) two-step nucleation-autocatalytic growth model to the concentration-dependent amyloid kinetics of proinflammatory alpha-helical S100A9 protein at pH 7.4 and at 37 and 42 degrees C. The model is based on two pseudoelementary reaction steps applied without further analytical constraints, and its treatment of S100A9 amyloid self-assembly demonstrates that initial misfolding and beta-sheet formation, defined as nucleation step, spontaneously takes place within individual S100A9 molecules at higher rate than the subsequent fibrillar growth. The latter, described as an autocatalytic process, will proceed if misfolded amyloid-prone S100A9 is populated on a macroscopic time scale. Short lengths of S100A9 fibrils are consistent with the F-W model. The analysis of fibrillar length distribution by the Beker-Doring model demonstrates independently that such distribution is solely determined by slow fibril growth and there is no fragmentation or secondary pathways decreasing fibrillar length.
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