Regulation of ApoE receptor proteolysis by ligand binding
Regulation of ApoE receptor proteolysis by ligand binding
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DOI：
10.1016/j.molbrainres.2005.02.013
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发表时间：
2005-06-13
期刊：
影响因子：
--
通讯作者：
Rebeck, GW
中科院分区：
文献类型：
--
作者：
Hoe, HS;Rebeck, GW
脑内两种载脂蛋白E受体--载脂蛋白E受体2(ApoER2)和极低密度脂蛋白受体(VLDLr)--在神经元发育过程中起着重要的迁移作用。利用一系列标记的结构，我们发现这两个受体经历了胞外切割以释放分泌形式的受体，以及膜内切割以降解C末端片段。胞外区的释放被金属蛋白酶抑制剂阻断，并被PMA促进。细胞内域的积累被伽马分泌酶抑制剂的存在所增加。APOE与这些受体的结合导致细胞外域的释放和细胞内域的积累；用apoE衍生的多肽处理原代神经元或大鼠海马区后，内源性ApoER2的受体蛋白水解域也出现了类似的增加。人apoE亚型在不同程度上促进了蛋白质的降解，与apoE4相比，apoE2导致apoER2的C末端片段的积累更多。载脂蛋白E对受体蛋白降解的这些作用是由受体的配体结合域介导的。另外两种配体--reelin和活化的α2-大球蛋白也同样促进了受体的切割。我们认为，由这些受体促进的信号部分依赖于这些受调控的蛋白分解事件。(C)2005 Elsevier B.V.保留所有权利。
Two brain receptors for apolipoprotein E (apoE), the apoE receptor 2 (apoEr2) and the very low density lipoprotein receptor (VLDLr), are important in neuronal migration during development. Using a series of tagged constructs, we found that these two receptors undergo extracellular cleavages to release secreted forms of the receptors and intramembranous cleavages to degrade the C-terminal fragments. Release of the extracellular domains was blocked by an inhibitor of metalloproteinases and increased by PMA. Accumulation of the intracellular domain was increased by the presence of an inhibitor of gamma-secretase. ApoE binding to these receptors caused increased release of the extracellular domain and accumulation of the intracellular domains; similar increases in receptor proteolytic domains were observed from endogenous apoEr2 after treatment of primary neurons or rat hippocampus with an apoE-derived peptide. The human apoE isoforms promoted proteolysis to different degrees, with apoE2 resulting in a greater accumulation of the C-terminal fragments of apoEr2 compared with apoE4. These effects of apoE on receptor proteolysis were mediated by the ligand binding domain of the receptor. Similar promotion of receptor cleavage was seen with two other ligands, reelin and activated alpha 2-macroglobutin. We suggest that signaling promoted by these receptors depends in part on these regulated proteolytic events. (c) 2005 Elsevier B.V. All rights reserved.