Function of neuron-specific X11L protein (human LIN10) and its concerning in neuraldegeneration

在阿尔茨海默病（AD）中，β-淀粉样肽（a β）被认为是APP异常代谢的结果。各种类型的蛋白质与APP细胞质结构域的这些基元相关，并调节APP的代谢、运输和功能。我们分离了新的APP结合蛋白X11L。X11L的磷酸酪氨酸相互作用域与APP的NPTY基序结合。这种相互作用稳定了APP的代谢，抑制了β-淀粉样蛋白的产生。为了分析X11L对APP代谢的调控机制，我们利用酵母双杂交系统分离X11L结合蛋白。我们发现了NF-_kB、XB51和与X11L相关的新型膜蛋白。X11L与这些蛋白的相互作用调节APP与X11L的关联，从而调节APP的代谢。APP在胞质域Thr668位点被磷酸化。这种磷酸化抑制了某些类型的结合，如APP结合物的Fe65与NPTY基序的结合。X11L不通过磷酸化影响其与APP的相互作用。X11L与APP细胞质结构域的结合稳定了APP的磷酸化水平。这些观察结果表明，X11L与APP的结合可以改变APP的代谢和功能。

In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) is thought to be produced as a results of the aberrant metabolism of APP. Various types of proteins associate with these motifs of APP cytoplasmic domain and modulate metabolism, trafficking and function of APP. We isolated novel APP binding protein, X11L. Phosphotyrosine interaction domain of X11L binds to NPTY motif of APP. This interaction stabilized the APP metabolism and results in the suppression of β-amyloid production. To analyze regulatory mechanism of X11L on APP metabolism, we isolated X11L binding proteins using Yeast two-hybrid system. We found NF-_kB, XB51, and novel membrane protein associated with X11L. Interaction of X11L with these proteins regulated association of APP with X11L resulting regulateion of APP metabolism.APP is phosphorylated at Thr668 in the cytoplasmic domain. This phosphorylation suppresses the associateion of some type such as Fe65 of APP binder to NPTY motif. X11L did not affect its interaction to APP by the phosphorylation. The binding of X11L to the cytoplasmic domain of APP stabilized the phosphorylation level of APP. These observations suggest that association of X11L with APP can modify the metabolism and function of APP.