Amyloid precursor protein associates independently and collaboratively with PTB and PDZ domains of mint on vesicles and at cell membrane
Amyloid precursor protein associates independently and collaboratively with PTB and PDZ domains of mint on vesicles and at cell membrane
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DOI：
10.1016/s0306-4522(01)00124-5
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发表时间：
2001-01-01
期刊：
影响因子：
3.3
通讯作者：
Sugita, M
中科院分区：
文献类型：
--
作者：
Okamoto, M;Nakajima, Y;Sugita, M
薄荷家族由从秀丽隐杆线虫到哺乳动物神经元的进化上保守的衔接蛋白组成。三种哺乳动物同种型。薄荷1、2和3在其N-末端的一半被广泛地转向，并且形成鲜明对比的是，在其C-末端的一半中彼此高度同源，所述C-末端的一半含有磷酸酪氨酸结合（PTB）和PSD-95/DLG-A/ZO-1（PDZ）结构域，其作为蛋白质-蛋白质相互作用模块起作用。生化和遗传分析表明，薄荷1和LIN-10。在C.线虫，包括在突触前和突触后末端的大分子复合物。从而将突触囊泡带到胞吐递质释放位点，并将受体和离子通道定位在特定的膜结构域中，淀粉样前体蛋白是薄荷PTB结构域的靶点之一，这种相互作用调节其蛋白水解过程，最终导致淀粉样β肽的产生，但其分子机制尚不清楚。我们展示;通过原位杂交技术，MINT 3（一种普遍存在的同种型）在小鼠脑中的极性细胞如神经元和非极性细胞如神经胶质和室管膜细胞中表达。此外，相当数量的人同源物mint 3（约70 kDa）在人上皮细胞系中表达。在细胞下。MINT 3特异性地富集在细胞质中的囊泡中。细胞膜和高尔基复合体作为储备。一系列的缺失或定点突变揭示了mint 3通过PTB和PDZb结构域独立和协同地双重识别含有淀粉样前体蛋白的大分子复合物。不仅在胞质转运囊泡中，甚至在淀粉样前体蛋白被靶向和/或插入到特定的细胞膜结构域之后，MINT 3也被激活，从这些结果我们认为MINT 3将淀粉样前体蛋白与其他组分连接起来。从而调节其运输。内吞作用和代谢。淀粉样前体蛋白代谢异常导致早发性阿尔茨海默病，但其分子机制尚未完全了解。目前的研究结果提供了形态学证据和分子框架的薄荷如何与淀粉样前体蛋白相互作用，并修改其加工的分泌途径。(C)2001年IBRO。由爱思唯尔科技有限公司出版。保留所有权利。
The mint family consists of evolutionarily conserved adapter proteins from Caenorhabditis elegans to mammalian neurons. Three mammalian isoforms. mint 1, 2, and 3, are extensively diverted in their N-terminal halves and, in striking contrast, are highly homologous to each other in their C-terminal halves containing phospho tyrosine-binding (PTB) and PSD-95/DLG-A/ZO-1 (PDZ) domains that work as protein-protein interaction modules. Biochemical and genetic analyses revealed that mint 1 and LIN-10. a homolog in C. elegans, comprise macromolecular complexes in the presynaptic and postsynaptic terminals. thereby bringing synaptic vesicles to the exocytotic transmitter release site and localizing receptors and ion channels in the specific membrane domains, Amyloid precursor protein is one of the targets of the PTB domain of mint and this interaction modulates its proteolytic procedures ending up with amyloid beta peptide production, but its molecular mechanism is unclear. We show; by an in situ hybridization technique that mint3, a ubiquitous isoform, is expressed both in polar cells like neurons, and in non-polar cells, such as glia and ependymal cells, in the mouse brain. In addition, a considerable amount of a human homolog mint3 ( approximate to 70 kDa) was expressed in a human epithelial cell line. Subcellularly. mint3 is specifically enriched in vesicles in the cytoplasm. cell membrane, and Golgi complex as reserves. A series of deletions or site-directed mutations revealed that mint3 double recognizes an amyloid precursor protein-containing macromolecular complex via the PTB and PDZb domains independently and cooperatively. not only in the cytoplasmic transporting vesicles but even after amyloid precursor protein was targeted and/or inserted to the specific: cell membrane domains.From these results we suggest that mint3 links amyloid precursor protein to other components. thereby regulating its transport. endocytosis, and metabolism. Abnormal metabolism of amyloid precursor protein causes an early-onset type of Alzheimer's disease bur its molecular mechanism is incompletely understood. The present findings give morphological evidence and a molecular framework of how mint interacts with amyloid precursor protein and modifies its processing on the secretor); pathway. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.