Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11
Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11
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DOI：
10.1021/bi052120v
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发表时间：
2006-02-28
期刊：
影响因子：
2.9
通讯作者：
Willnow, TE
中科院分区：
文献类型：
--
作者：
Andersen, OM;Schmidt, V;Willnow, TE
SorLA/LR 11是一种分选受体，调节神经元中淀粉样前体蛋白（APP）的细胞内转运和加工。SorLA/LR 11介导的结合导致APP在高尔基体中的隔离，并防止加工成淀粉样β肽（A β），淀粉样β肽是阿尔茨海默病（AD）中老年斑的主要成分。为了深入了解sorLA和APP相互作用的分子机制，我们解剖了各自的蛋白质相互作用域。使用基于荧光共振能量转移（FRET）的蛋白质接近性测定，我们确定了两种蛋白质的细胞外区域中的结合位点。精细映射的表面等离子体共振分析和分析ultracentraggation的重组APP和sorLA片段进一步缩小了结合域的互补型重复序列的簇sorLA，形成一个1：1的化学计量复合物与碳水化合物的inked结构域的APP。这些数据揭示了新的光神经元APP的贩运和加工的分子决定因素和可能的目标与老年斑的形成与AD患者的干预。
SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of the amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results in sequestration of APP in the Golgi and in protection from processing into the amyloid-beta peptide (A beta), the principal component of senile plaques in Alzheimer's disease (AD). To gain insight into the molecular mechanisms governing sorLA and APP interaction, we have dissected the respective protein interacting domains. Using a fluorescence resonance energy transfer (FRET) based assay of protein proximity, we identified binding sites in the extracellular regions of both proteins. Fine mapping by surface plasmon resonance analysis and analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex with the carbohydrated inked domain of APP. These data shed new light on the molecular determinants of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque formation in patients with AD.