Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia

Omar Ali El-Agnaf, J. M. Sheridan, C. Sidera, G. Siligardi, R. Hussain, P. I. Haris, B. M. Austen

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 β-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three β-strands, and two β-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.

Original languageEnglish
Pages (from-to)3449-3457
Number of pages9
JournalBiochemistry
Volume40
Issue number12
DOIs
Publication statusPublished - 27 Mar 2001
Externally publishedYes

Fingerprint

Abrus
Oligomerization
Amyloid
Disulfides
Amyloid Plaques
Peptides
Protein Precursors
Oligomers
Amino Acids
Deposits
Furin
Dimers
Neurofibrillary Tangles
Molecular Models
Brain
Terminator Codon
Genes
Familial British Dementia
Point Mutation
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia. / Ali El-Agnaf, Omar; Sheridan, J. M.; Sidera, C.; Siligardi, G.; Hussain, R.; Haris, P. I.; Austen, B. M.

In: Biochemistry, Vol. 40, No. 12, 27.03.2001, p. 3449-3457.

Research output: Contribution to journalArticle

Ali El-Agnaf, Omar ; Sheridan, J. M. ; Sidera, C. ; Siligardi, G. ; Hussain, R. ; Haris, P. I. ; Austen, B. M. / Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia. In: Biochemistry. 2001 ; Vol. 40, No. 12. pp. 3449-3457.
@article{dae0d6a07b04456c819457102fc5f970,
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 β-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three β-strands, and two β-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.",
author = "{Ali El-Agnaf}, Omar and Sheridan, {J. M.} and C. Sidera and G. Siligardi and R. Hussain and Haris, {P. I.} and Austen, {B. M.}",
year = "2001",
month = "3",
day = "27",
doi = "10.1021/bi002287i",
language = "English",
volume = "40",
pages = "3449--3457",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "12",

}

TY - JOUR

T1 - Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia

AU - Ali El-Agnaf, Omar

AU - Sheridan, J. M.

AU - Sidera, C.

AU - Siligardi, G.

AU - Hussain, R.

AU - Haris, P. I.

AU - Austen, B. M.

PY - 2001/3/27

Y1 - 2001/3/27

N2 - 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 β-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three β-strands, and two β-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.

AB - 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 β-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three β-strands, and two β-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.

UR - http://www.scopus.com/inward/record.url?scp=0035957220&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035957220&partnerID=8YFLogxK

U2 - 10.1021/bi002287i

DO - 10.1021/bi002287i

M3 - Article

VL - 40

SP - 3449

EP - 3457

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 12

ER -