The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate
The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate
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DOI：
10.1074/jbc.m414248200
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发表时间：
2005-05-06
影响因子：
4.8
通讯作者：
Hyman, BT
中科院分区：
文献类型：
--
作者：
von Arnim, CAF;Kinoshita, A;Hyman, BT
BACE是一种具有β-分泌酶活性的跨膜蛋白酶，可切割淀粉样前体蛋白（APP）。在BACE裂解后，APP成为γ-分泌酶的底物，导致淀粉样β肽（A β）的释放，其在阿尔茨海默病的老年斑中积累。APP和BACE从细胞表面共内化至早期内体。APP还已知在细胞表面相互作用，并被低密度脂蛋白受体相关蛋白（LRP）内化，LRP是一种多功能内吞和信号受体。使用一种新的荧光共振能量转移（FRET）为基础的蛋白质接近，荧光寿命成像（FLIM），和免疫共沉淀的测定，我们证明LRP的轻链与BACE在细胞表面与脂筏相互作用。令人惊讶的是，BACE-LRP相互作用导致LRP C末端片段增加，分泌的LRP在培养基中释放，随后LRP胞内结构域从膜释放。综上所述，这些数据表明BACE和LRP之间在细胞表面上存在密切的相互作用，并且LRP是一种新的BACE底物。
BACE is a transmembrane protease with beta-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for gamma-secretase, leading to release of amyloid-beta peptide (A beta), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer ( FRET)based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.