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Effects of the H6R and D7H Mutations on the Heparin-Dependent Modulation of Zinc-Induced Aggregation of Amyloid β

  • STRUCTURAL-FUNCTIONAL ANALYSIS OF BIOPOLYMERS AND THEIR COMPLEXES
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Abstract

Zinc ions and glycosaminoglycans (GAGs) are found in amyloid deposits and are known to modulate the β-amyloid peptide (Аβ) aggregation, which is thought to be a key event in the pathogenesis of Alzheimer’s disease (AD). Correlation spectroscopy was used to study how the H6R and D7H mutations of the metal-binding domain (MBD) of Аβ42 affect the modulation of its zinc-induced aggregation by the model GAG heparin. The H6R mutation was shown to decrease and the D7H mutation to increase the Аβ42 propensity to aggregate in the presence of zinc ions. In addition, H6R diminished and D7H enhanced the modulating effect of heparin. The difference in the heparin-dependent modulation was associated with coordination of zinc ions within the MBDs of the mutant peptides. The findings indicate that anion-binding sites formed by complexes of zinc ions with the Аβ MBD play an essential role in the interaction of zinc-induced Аβ aggregates with heparin.

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ACKNOWLEDGMENTS

We used equipment of the Human Proteome Collective Access Center (Orekhovich Institute of Biomedical Chemistry).

Funding

This work was supported by the program “Basic Research for Biomedical Technologies” of the Presidium of the Russian Academy of Sciences.

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia

    S. P. Radko, S. A. Kozin, V. A. Mitkevich & A. A. Makarov

  2. Orekhovich Institute of Biomedical Chemistry, 119121, Moscow, Russia

    S. P. Radko & S. A. Khmeleva

  3. Russian Scientific Center of Roentgenoradiology, 117485, Moscow, Russia

    Y. Y. Kiseleva

Authors
  1. S. P. Radko
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  2. S. A. Khmeleva
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  3. Y. Y. Kiseleva
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  4. S. A. Kozin
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  5. V. A. Mitkevich
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  6. A. A. Makarov
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Correspondence to S. P. Radko.

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The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

Additional information

Translated by T. Tkacheva

Abbreviations: AD, Alzheimer’s disease; GAG, glycosaminoglycan; Aβ, amyloid β; MBD, metal-binding domain; a.a., amino acid residue.

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Radko, S.P., Khmeleva, S.A., Kiseleva, Y.Y. et al. Effects of the H6R and D7H Mutations on the Heparin-Dependent Modulation of Zinc-Induced Aggregation of Amyloid β. Mol Biol 53, 922–928 (2019). https://doi.org/10.1134/S0026893319060141

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  • DOI: https://doi.org/10.1134/S0026893319060141

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