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衔接蛋白 2 介导的β-分泌酶 BACE1 的内吞作用对于淀粉样前体蛋白的加工是可有可无的。

Adaptor protein 2-mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing.

机构信息

Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

Mol Biol Cell. 2012 Jun;23(12):2339-51. doi: 10.1091/mbc.E11-11-0944. Epub 2012 May 2.

Abstract

The β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER-Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

摘要

β-淀粉样前体蛋白(APP)裂解酶 1(BACE1)是一种跨膜天冬氨酸蛋白酶,可催化 APP 和其他质膜蛋白前体的蛋白水解加工。BACE1 通过其胞质 C 末端结构域中的信号在转高尔基网络(TGN)、质膜和内体之间循环。这些信号之一是 DXXLL 基序序列 DISLL,它通过与 GGA 蛋白相互作用控制 TGN 和内体之间的运输。在这里,我们表明 DISLL 序列嵌入在更长的 [DE]XXXL[LI]-基序序列 DDISLL 中,该序列通过与网格蛋白相关的异四聚体衔接蛋白 2(AP-2)复合物相互作用介导从质膜内化。该信号的突变或 AP-2 或网格蛋白的敲低会减少内体定位并增加 BACE1 的质膜定位。值得注意的是,内化缺陷的 BACE1 能够切割自身不能递送至内体的 APP 突变体。药物布雷菲德菌素 A 可逆地阻止 BACE1 催化的 APP 裂解,排除该反应发生在内质网(ER)或 ER-高尔基体中间隔室中。综上所述,这些观察结果支持 BACE1 能够在分泌途径的晚期隔室中切割 APP 的观点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94c7/3374752/33b17221b251/2339fig1.jpg

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