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Finke-Watzky Two-Step Nucleation-Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as "Nucleation" Event.

Authors :
Iashchishyn IA
Sulskis D
Nguyen Ngoc M
Smirnovas V
Morozova-Roche LA
Source :
ACS chemical neuroscience [ACS Chem Neurosci] 2017 Oct 18; Vol. 8 (10), pp. 2152-2158. Date of Electronic Publication: 2017 Aug 03.
Publication Year :
2017

Abstract

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 α-helical S100A9 protein at pH 7.4 and at 37 and 42 °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 β-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-Döring model demonstrates independently that such distribution is solely determined by slow fibril growth and there is no fragmentation or secondary pathways decreasing fibrillar length.

Details

Language :
English
ISSN :
1948-7193
Volume :
8
Issue :
10
Database :
MEDLINE
Journal :
ACS chemical neuroscience
Publication Type :
Academic Journal
Accession number :
28759719
Full Text :
https://doi.org/10.1021/acschemneuro.7b00251