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首页> 外文期刊>Biochemistry >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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Effect of the Disulfide Bridge and the C-Terminal Extension on the Oligomerization of the Amyloid Peptide ABri Implicated in Familial British Dementia

机译：二硫化物桥和C末端延伸对家族性英国痴呆症含有淀粉样蛋白肽ABRI的寡聚化的影响

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摘要

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 llsual 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-terrninal extension are required to elongate initially formed dimmers to oligomers and Fibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformational malyses indicate that the disulfide bond and the C-terrninal extension of ABri are required for the formation )f f3-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature Fibrils. A molecular model of ABri containing three f3-strands, and two f3-hairpins annealed by a disulfide )ond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.
机译：家族性英国痴呆症（FBD）是一种罕见的神经退行性疾病，具有阿尔茨海默病的股份，包括淀粉样蛋白斑块沉积物，神经纤维缠结，神经元损失和进行性痴呆。 FBD大脑的斑块和血管淀粉样蛋白的免疫组织化学和生化分析表明，4 kda肽名为abri是高度不溶性淀粉样液沉积物的主要成分。在FBD患者中，由于BRI基因的LLSUAL止芯密码子中的点突变而产生ABRI肽。该突变产生比野生型蛋白质长的BRI前体蛋白11氨基酸。突变体和野生型前体蛋白在残留物243和244之间经过Furin切割，在野生型（WT）肽的情况下，在ABRI和23个氨基酸的情况下产生34个氨基酸的肽。在这里，我们证明了ABRI和C局延伸的分子内二硫化粘合剂需要延长最初形成的调光器，以寡聚体和原纤维。相反，较短的WT肽在相同条件下不会聚集。构象性小麦表明形成的二硫键和ABRI的C局部延长是形成的F F3-片状结构。在成熟的原纤维外观之前观察到可溶性非纤维酒ABRIGOMERS。已经构建了含有三种F3-股和二硫化物退火的两个F3发夹的ABRI的分子模型，并预测疏水表面，该疏水表面是促进寡聚化的辅助。

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  • 来源
    《Biochemistry》 |2001年第12期|共9页
  • 作者

    Omar M.A.El-Agnaf; Joseph M.Sheridan; Christina Sidera; Giuliano Siligardi; Rohanah Hussain; Parvez I.Haris; Brian M.Austen;

  • 作者单位

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

    Neurodegeneration Unit Department of Surgery St. George's Hospital Medical School Cranmer Terrace Tooting London SW17 0RE U.K. Department of Pharmacy King's College Franklin-Wilkins Building 150 Stamford Street. London SW1 8WA U.K. and Departm;

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  • 正文语种 eng
  • 中图分类 生物化学;
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