Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-ß Peptides.
J Alzheimers Dis
; 63(2): 539-550, 2018.
Article
em En
| MEDLINE
| ID: mdl-29630553
ABSTRACT
Zinc-induced aggregation of amyloid-ß peptides (Aß) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aß self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous Aß aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aß42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aß16 peptides to model the Aß metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aß42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aß42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aß42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aß16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aß aggregation.
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MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Zinco
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Peptídeos beta-Amiloides
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article