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High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications.

Corbacho, I; Berrocal, M; Török, K; Mata, AM; Gutierrez-Merino, C (2017) High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications. Biochem Biophys Res Commun, 486 (4). pp. 992-997. ISSN 1090-2104 https://doi.org/10.1016/j.bbrc.2017.03.151
SGUL Authors: Torok, Katalin

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Abstract

Amyloid β-peptides (Aβ) are a major hallmark of Alzheimer's disease (AD) and their neurotoxicity develop with cytosolic calcium dysregulation. On the other hand, calmodulin (CaM), a protein which plays a major multifunctional role in neuronal calcium signaling, has been shown to be involved in the regulation of non-amyloidogenic processing of amyloid β precursor protein (APP). Using fluorescent 6-bromoacetyl-2-dimethylaminonaphthalene derivatives of CaM, Badan-CaM, and human amyloid β(1-42) HiLyte™-Fluor555, we show in this work that Aβ binds with high affinity to CaM through the neurotoxic Aβ25-35 domain. In addition, the affinity of Aβ for calcium-saturated CaM conformation is approximately 20-fold higher than for CaM conformation in the absence of calcium (apo-CaM). Moreover, the value of Kd of 0.98 ± 0.11 nM obtained for Aβ1-42 dissociation from CaM saturated by calcium point out that CaM is one of the cellular targets with highest affinity for neurotoxic Aβ peptides. A major functional consequence of Aβ-CaM interaction is that it slowdowns Aβ fibrillation. The novel and high affinity interaction between calmodulin and Aβ shown in this work opens a yet-unexplored gateway to further understand the neurotoxic effect of Aβ in different neural cells and also to address the potential of calmodulin and calmodulin-derived peptides as therapeutic agents in AD.

Item Type: Article
Additional Information: © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Alzheimer's disease, Amyloid β, Badan-calmodulin, Calcium, Calmodulin, Human amyloid β (1-42) HiLyte™-Fluor555, Biochemistry & Molecular Biology, 0304 Medicinal And Biomolecular Chemistry, 0601 Biochemistry And Cell Biology, 1101 Medical Biochemistry And Metabolomics
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Biochem Biophys Res Commun
ISSN: 1090-2104
Language: eng
Dates:
DateEvent
13 May 2017Published
29 March 2017Published Online
27 March 2017Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
PubMed ID: 28363865
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108758
Publisher's version: https://doi.org/10.1016/j.bbrc.2017.03.151

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