title: Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia.
abstract: Familial British dementia (FBD) is a rare neurodegenerative disorder and shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, and progressive dementia. Immunohistochemical and biochemical analysis of plaques and vascular amyloid of FBD brains revealed that a 4 kDa peptide named ABri is the main component of the highly insoluble amyloid deposits. In FBD patients, the ABri peptide is produced as a result of a point mutation in the usual stop codon of the BRI gene. This mutation produces a BRI precursor protein 11 amino acids longer than the wild-type protein. Mutant and wild-type precursor proteins both undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids in the case of the wild-type (WT) peptide. Here we demonstrate that the intramolecular disulfide bond in ABri and the C-terminal extension are required to elongate initially formed dimers to oligomers and fibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformational analyses indicate that the disulfide bond and the C-terminal extension of ABri are required for the formation of beta-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three beta-strands, and two beta-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.
authors: Neurodegeneration Unit, Department of Surgery, St. George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK. oelagnaf@sghms.ac.uk
authors: O M
authors: OM
authors: El-Agnaf
authors: J M
authors: JM
authors: Sheridan
authors: C
authors: C
authors: Sidera
authors: G
authors: G
authors: Siligardi
authors: R
authors: R
authors: Hussain
authors: P I
authors: PI
authors: Haris
authors: B M
authors: BM
authors: Austen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D001665:Binding Sites / Q000235:genetics; D002942:Circular Dichroism; D004396:Coloring Agents; D003224:Congo Red / Q000378:metabolism; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017433:Protein Structure, Secondary / Q000235:genetics; D012996:Solutions; D017550:Spectroscopy, Fourier Transform Infrared; D006113:United Kingdom
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D004396:Coloring Agents; D004220:Disulfides; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D012996:Solutions; D003224:Congo Red