Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
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DOI：
10.1038/s41598-017-12334-2
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发表时间：
2017-09-29
影响因子：
4.6
通讯作者：
Lau, Kwok-Fai
中科院分区：
文献类型：
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作者：
Lee, Yat Shing;Chow, Wan Ning Vanessa;Lau, Kwok-Fai
淀粉样前体蛋白（APP）的异常蛋白水解导致淀粉样β肽（A β）的过度生成是阿尔茨海默病（AD）发病机制中的关键事件。FE 65是一种脑富集的磷酸适配蛋白，与APP相互作用，并已被证明可以调节APP加工。然而，FE 65改变APP处理的机制仍然没有完全理解。在本研究中，我们证明FE 65是磷酸化的苏氨酸579（T579）的糖原合成酶激酶3 β（GSK 3 β）。此外，FE 65 T579磷酸化增强α和β分泌酶介导的APP加工和A β释放。此外，磷酸化抑制FE 65 PTB 2分子间二聚化，但增强FE 65/APP复合物的形成。因此，我们的研究结果揭示了一种新的机制，即GSK 3 β通过T579处的FE 65磷酸化刺激APP的淀粉样蛋白加工。
Excessive generation of amyloid-beta peptide (A beta) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phosphoadaptor protein that interacts with APP and has been shown to modulate APP processing. However, the mechanism(s) that FE65 alters APP processing is still not fully understood. In the present study, we demonstrate that FE65 is phosphorylated at threonine 579 (T579) by glycogen synthase kinase 3 beta (GSK3 beta). Moreover, FE65 T579 phosphorylation potentiates alpha- and beta-secretases-mediated APP processing and A beta liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3 beta stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579.