Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2
Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2
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DOI：
10.1034/j.1600-0854.2001.020206.x
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发表时间：
2001-02-01
期刊：
影响因子：
4.5
通讯作者：
Cooper, JA
中科院分区：
文献类型：
--
作者：
Morris, SM;Cooper, JA
DISABLED-2(DAB2)是DISABLED-1的一个广泛表达的亲属，DISABLED-1是一种神经元特异性信号转导蛋白，与低密度脂蛋白受体(LDLR)家族成员结合并接受来自该家族成员的信号。低密度脂蛋白受体家族的成员通过包被网状蛋白的凹坑和囊泡内化到内小体，在那里他们通过分泌途径返回细胞表面。在本研究中，我们发现DAB2磷酸酪氨酸结合区与含有序列FXN-PXY的多肽结合。该核心序列存在于LDLR家族成员的胞内结构域中，对受体内化具有重要作用。DAB2与LDLR在包被网壳蛋白的小孔中短暂共存，但在内体和溶酶体中不存在。DAB2是选择性剪接的，其定位取决于蛋白质的一个区域，该区域包含两个DPF基序，这两个基序存在于p96 DAB2蛋白中，而不存在于p67剪接变体中。这一区域足以使DAB2与网状蛋白AP-2的α-Adaptin亚基结合。P96的过表达而不是p67 DAB2的过表达扰乱了AP-2的定位。这些发现表明，除了先前报道的信号转导功能外，DAB2还可以作为一种适配蛋白，可能调节蛋白质的运输。
Disabled-2 (Dab2) is a widely expressed relative of Disabled-1, a neuron-specific signal-transduction protein that binds to and receives signals from members of the low-density lipoprotein receptor (LDLR) family. Members of the LDLR family internalize through clathrin-coated pits and vesicles to endosomes, from where they return to the cell surface through the secretory pathway. In this study, we show that the Dab2 phosphotyrosine-binding domain binds peptides containing the sequence FXN-PXY. This core sequence is found in the intracellular domains of LDLR family members and is important for receptor internalization. Dab2 transiently colocalizes with the LDLR in clathrin-coated pits, but is absent from endosomes and lysosomes. Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha -adaptin subunit of the clathrin adaptor protein, AP-2. Overexpression of p96 but not of p67 Dab2 disrupts the localization of AP-2. These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking.