BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid β (Aβ) production
BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid β (Aβ) production
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DOI：
10.1074/jbc.c500231200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
Efthimiopoulos, S
中科院分区：
文献类型：
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作者：
Fotinopoulou, A;Tsachaki, M;Efthimiopoulos, S
在散发性阿尔茨海默病中，跨膜蛋白BRI2和淀粉样蛋白前体蛋白（APP）与淀粉样蛋白β (A β)病变共定位，这两种前体蛋白的突变与痴呆和/或脑出血相关的早发性脑淀粉样变性家族性病例有关。通过转染细胞和未转染细胞的免疫沉淀实验，揭示了BRI2和APP之间的特异性相互作用。缺失突变体的使用进一步表明，APP751的648-719和BRI2的46-106片段都包含完整的跨膜结构域，足以进行相互作用。去除大部分APP和BRI2胞外结构域而不影响相互作用意味着这两种蛋白在同一细胞膜上表达时（顺式）而不是在相邻细胞上表达时（反式）相互作用。BRI2的存在对APP加工具有调节作用，特别是增加了细胞APP和β -分泌酶产生的cooh末端片段的水平，同时降低了α -分泌酶产生的cooh末端片段的水平以及总APP和a- β肽的分泌。确定APP与BRI2特异性结合影响的精确分子通路，可能有助于确定这些散发性和家族性神经退行性疾病的共同治疗靶点。
Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid beta(A beta) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648-719 of APP751 and 46-106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as beta-secretase-generated COOH-terminal fragments while decreasing the levels of alpha-secretase-generated COOH-terminal fragments as well as the secretion of total APP and A beta peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders.