Ca(2+) Interacts with Glu-22 of Aß(1-42) and Phospholipid Bilayers to Accelerate the Aß(1-42) Aggregation Below the Critical Micelle Concentration.
Biochemistry
; 54(41): 6323-32, 2015 Oct 20.
Article
em En
| MEDLINE
| ID: mdl-26426973
ABSTRACT
The amyloid cascade hypothesis links the amyloid-ß (Aß) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer's disease (AD). Although Aß aggregation has been known to accelerate at cell membranes, the exact mechanism of Aß peptide deposition and the involvement of extracellular species are still largely unclear. Using surface plasmon resonance (SPR) and atomic force microscopy (AFM), we demonstrate that Ca(2+) ions, in conjunction with lipid bilayer, lower the threshold concentration for Aß aggregation (>a few micromolar in vitro) to physiological levels (low nanomolar). Circular dichroism spectroscopy reveals that Ca(2+) ions and the lipid bilayer concertedly accelerate the conformational change or misfolding of Aß peptides. Molecular dynamics calculation indicates that Ca(2+) is sandwiched between Glu-22 of Aß and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca(2+), Aß(1-42), and the phospholipid bilayer. With the C- and N-termini of the Aß dimer fully exposed for the attachment of additional Aß molecules, fibrils formed with the Ca(2+)-anchored Aß nuclei appear to interact with lipid bilayers differently from those preformed in solution. Thus, similar to the role of Ca(2+) in enriching islet amyloid polypeptides in the pancreas of diabetic patients ( Biophys. J. 2013 , 104 , 173 - 184 ) and the "Ca(2+) bridge" in mediating membrane interaction with α-synuclein in the Parkinson's disease ( Biochemistry , 2006 , 45 , 10947 - 10956 ), the influence of Ca(2+) on the Aß adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Fosfolipídeos
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Cálcio
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Peptídeos beta-Amiloides
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Agregados Proteicos
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Bicamadas Lipídicas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article