title: High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications.
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 Kdof 0.98 ± 0.11 nM obtained for Aβ1-42 dissociation from CaM saturated by calcium points 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.
authors.affiliation: Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, Avda. de Elvas, s/n, 06006 Badajoz, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Corbacho
authors.affiliation: Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, Avda. de Elvas, s/n, 06006 Badajoz, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Berrocal
authors.affiliation: Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Katalin
authors.initials: K
authors.lastname: Török
authors.affiliation: Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, Avda. de Elvas, s/n, 06006 Badajoz, Spain. Electronic address: anam@unex.es.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Mata
authors.affiliation: Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, Avda. de Elvas, s/n, 06006 Badajoz, Spain. Electronic address: carlosgm@unex.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gutierrez-Merino
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry*; D002147:Calmodulin / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002147:Calmodulin; D002118:Calcium
keywords: Alzheimer's disease; Amyloid β; Badan-calmodulin; Calcium; Calmodulin; Human amyloid β (1-42) HiLyte™-Fluor555