Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA
Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA
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DOI：
10.1128/mcb.00815-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Petersen, Claus M.
中科院分区：
文献类型：
--
作者：
Nielsen, Morten S.;Gustafsen, Camilla;Petersen, Claus M.
SorLA/LR11（250 kDa）是Vps10p结构域受体中最大和最复杂的成员，Vps10p结构域受体是优先在神经元组织中表达的1型蛋白家族。SorLA结合几种配体，包括神经降压素、血小板衍生生长因子-bb和脂蛋白脂肪酶，并且通过与淀粉样前体蛋白形成复合物，其下调阿尔茨海默病相关A β肽的产生。该受体主要位于囊泡中，表明其在蛋白质分选和转运中起作用。在这里，我们研究了SorLA的贩运使用全长和嵌合受体，并发现其胞质尾介导有效的高尔基体内体运输，以及AP-2复合物依赖的内吞作用。功能性分选位点被映射到酸性簇双亮氨酸样基序和C末端的GGA结合位点。在永久性或暂时性AP-1 μ 1链缺陷细胞中的实验表明，AP-1接头复合物对SorLA在高尔基体膜和内体之间的运输是必不可少的。我们的研究结果进一步牵连的GGA蛋白在SorLA运输和提供的证据表明，SNX1和Vps35，作为一部分的retromer复合物或可能在一个单独的情况下，从事从内体的受体的回缩。
SorLA/LR11 (250 kDa) is the largest and most composite member of the Vps10p-domain receptors, a family of type 1 proteins preferentially expressed in neuronal tissue. SorLA binds several ligands, including neurotensin, platelet-derived growth factor-bb, and lipoprotein lipase, and via complex-formation with the amyloid precursor protein it downregulates generation of Alzheimer's disease-associated A beta-peptide. The receptor is mainly located in vesicles, suggesting a function in protein sorting and transport. Here we examined SorLA's trafficking using full-length and chimeric receptors and find that its cytoplasmic tail mediates efficient Golgi body-endosome transport, as well as AP-2 complex-dependent endocytosis. Functional sorting sites were mapped to an acidic cluster-dileucine-like motif and to a GGA binding site in the C terminus. Experiments in permanently or transiently AP-1 mu 1-chain-deficient cells established that the AP-1 adaptor complex is essential to SorLA's transport between Golgi membranes and endosomes. Our results further implicate the GGA proteins in SorLA trafficking and provide evidence that SNX1 and Vps35, as parts of the retromer complex or possibly in a separate context, are engaged in retraction of the receptor from endosomes.