Title of article :
pH-Dependent Amyloid and Protofibril Formation by the ABri Peptide of Familial British Dementia
Author/Authors :
Rekha Srinivasan، نويسنده , , Eric M. Jones، نويسنده , , Keqian Liu، نويسنده , , Jorge Ghiso، نويسنده , , Roger E. Marchant، نويسنده , , Michael G. Zagorski، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2003
Pages :
21
From page :
1003
To page :
1023
Abstract :
The ABri is a 34 residue peptide that is the major component of amyloid deposits in familial British dementia. In the amyloid deposits, the ABri peptide adopts aggregated β-pleated sheet structures, similar to those formed by the Aβ peptide of Alzheimerʹs disease and other amyloid forming proteins. As a first step toward elucidating the molecular mechanisms of the β-amyloidosis, we explored the ability of the environmental variables (pH and peptide concentration) to promote β-sheet fibril structures for synthetic ABri peptides. The secondary structures and fibril morphology were characterized in parallel using circular dichroism, atomic force microscopy, negative stain electron microscopy, Congo red, and thioflavin-T fluorescence spectroscopic techniques. As seen with other amyloid proteins, the ABri fibrils had characteristic binding with Congo red and thioflavin-T, and the relative amounts of β-sheet and amyloid fibril-like structures are influenced strongly by pH. In the acidic pH range 3.1–4.3, the ABri peptide adopts almost exclusively random structure and a predominantly monomeric aggregation state, on the basis of analytical ultracentrifugation measurements. At neutral pH, 7.1–7.3, the ABri peptide had limited solubility and produced spherical and amorphous aggregates with predominantly β-sheet secondary structure, whereas at slightly acidic pH, 4.9, spherical aggregates, intermediate-sized protofibrils, and larger-sized mature amyloid fibrils were detected by atomic force microscopy. With aging at pH 4.9, the protofibrils underwent further association and eventually formed mature fibrils. The presence of small amounts of aggregated peptide material or seeds encourage fibril formation at neutral pH, suggesting that generation of such seeds in vivo could promote amyloid formation. At slightly basic pH, 9.0, scrambling of the Cys5–Cys22 disulfide bond occurred, which could lead to the formation of covalently linked aggregates. The presence of the protofibrils and the enhanced aggregation at slightly acidic pH is consistent with the behavior of other amyloid-forming proteins, which supports the premise that a common mechanism may be involved in protein misfolding and β-amyloidosis.
Keywords :
British , fibril , structure , amyloid , amyloidogenesis
Journal title :
Journal of Molecular Biology
Serial Year :
2003
Journal title :
Journal of Molecular Biology
Record number :
1243154
Link To Document :
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