Effect of the Disulfide Bridge and the C-Terminal Extension on the Oligomerization of the Amyloid Peptide ABri Implicated in Familial British Dementia

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• 作者：Omar M. A. El-Agnaf ; Joseph M. Sheridan ; Christina Sidera ; Giuliano Siligardi ; Rohanah Hussain ; Parvez I. Haris ; and Brian M. Austen
• 刊名：Biochemistry
• 出版年：2001
• 出版时间：March 27, 2001
• 年：2001
• 卷：40
• 期：12
• 页码：3449 - 3457
• 全文大小：1093K
• 年卷期：v.40,no.12(March 27, 2001)
• ISSN：1520-4995

文摘

Familial British dementia (FBD) is a rare neurodegenerative disorder and shares features withAlzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, andprogressive dementia. Immunohistochemical and biochemical analysis of plaques and vascular amyloidof FBD brains revealed that a 4 kDa peptide named ABri is the main component of the highly insolubleamyloid deposits. In FBD patients, the ABri peptide is produced as a result of a point mutation in theusual stop codon of the BRI gene. This mutation produces a BRI precursor protein 11 amino acids longerthan the wild-type protein. Mutant and wild-type precursor proteins both undergo furin cleavage betweenresidues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids inthe case of the wild-type (WT) peptide. Here we demonstrate that the intramolecular disulfide bond inABri and the C-terminal extension are required to elongate initially formed dimers to oligomers andfibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformationalanalyses indicate that the disulfide bond and the C-terminal extension of ABri are required for the formationof -sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of maturefibrils. A molecular model of ABri containing three -strands, and two -hairpins annealed by a disulfidebond, has been constructed, and predicts a hydrophobic surface which is instrumental in promotingoligomerization.