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首页> 外文期刊>Molecular and Cellular Biology >The Disabled 1 Phosphotyrosine-Binding Domain Binds to the Internalization Signals of Transmembrane Glycoproteins and to Phospholipids
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The Disabled 1 Phosphotyrosine-Binding Domain Binds to the Internalization Signals of Transmembrane Glycoproteins and to Phospholipids

机译：残疾的1磷酸酪氨酸结合域绑定到跨膜糖蛋白和磷脂的内在信号。

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摘要

Disabled gene products are important for nervous system development in drosophila and mammals. In mice, the Dab1 protein is thought to function downstream of the extracellular protein Reln during neuronal positioning. The structures of Dab proteins suggest that they mediate protein-protein or protein-membrane docking functions. Here we show that the amino-terminal phosphotyrosine-binding (PTB) domain of Dab1 binds to the transmembrane glycoproteins of the amyloid precursor protein (APP) and low-density lipoprotein receptor families and the cytoplasmic signaling protein Ship. Dab1 associates with the APP cytoplasmic domain in transfected cells and is coexpressed with APP in hippocampal neurons. Screening of a set of altered peptide sequences showed that the sequence GYXNPXY present in APP family members is an optimal binding sequence, with approximately 0.5 μM affinity. Unlike other PTB domains, the Dab1 PTB does not bind to tyrosine-phosphorylated peptide ligands. The PTB domain also binds specifically to phospholipid bilayers containing phosphatidylinositol 4P (PtdIns4P) or PtdIns4,5P2 in a manner that does not interfere with protein binding. We propose that the PTB domain permits Dab1 to bind specifically to transmembrane proteins containing an NPXY internalization signal.
机译：禁用的基因产物对于果蝇和哺乳动物的神经系统发育很重要。在小鼠中，Dab1蛋白被认为在神经元定位过程中在细胞外蛋白Reln的下游起作用。 Dab蛋白的结构表明它们介导蛋白-蛋白或蛋白-膜对接功能。在这里，我们显示Dab1的氨基末端磷酸酪氨酸结合（PTB）域与淀粉样蛋白前体蛋白（APP）和低密度脂蛋白受体家族的跨膜糖蛋白以及细胞质信号蛋白Ship结合。 Dab1在转染的细胞中与APP胞质域相关，并在海马神经元中与APP共表达。一组改变的肽序列的筛选显示存在于APP家族成员中的序列GYXNPXY是最佳结合序列，具有约0.5μM的亲和力。与其他PTB域不同，Dab1 PTB不结合酪氨酸磷酸化的肽配体。 PTB结构域还以不干扰蛋白质结合的方式与含有磷脂酰肌醇4P（PtdIns4P）或PtdIns4,5P 2 的磷脂双层特异性结合。我们建议PTB域允许Dab1专门绑定到包含NPXY内部化信号的跨膜蛋白。

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