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Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs

Cite this: ACS Chem. Biol. 2019, 14, 7, 1410–1417
Publication Date (Web):June 5, 2019
Copyright © 2019 American Chemical Society

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    Abstract Image

    Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from Aβ peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self-assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.9b00394.

    • Details on experimental methods; details on AFM imaging of S100A9 amyloids in the absence and presence of NCAM1 constructs (Figure S1); AFM images of amyloid clumps formed at a 1:1 molar ratio of S100A9 with NCAM1-PrP and by S100A9 alone (Figure S2); incubation of NCAM1 and KKLVFF alone, as well as of the mixtures of S100A9 with NCAM1 or KKLVFF peptides monitored by ThT fluorescence and AFM imaging (Figure S3); magnified views of the interacting areas of S100A9 with NCAM1 constructs produced by all-atom MD simulations and complementary to Figure 3 (Figure S4); primary sequences, pI, and molecular weights of S100A9, NCAM1, peptides, and NCAM1 constructs (Table S1) (PDF)

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    Cited By

    This article is cited by 12 publications.

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