Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of β-amyloid
Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of β-amyloid
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DOI：
10.1074/jbc.m104059200
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发表时间：
2001-10-26
影响因子：
4.8
通讯作者：
Suzuki, T
中科院分区：
文献类型：
--
作者：
Ando, K;Iijima, K;Suzuki, T
神经元Fe65是一种与β-淀粉样前体蛋白(APP)的胞浆结构域相互作用的适配蛋白。虽然已经报道了Fe65的第二个磷酸酪氨酸相互作用结构域与APP细胞质结构域中的YENPTY基序之间存在相互作用，但这种相互作用的调节机制和生物学功能尚不清楚。我们在这里报道了APP695的Thr-668残基上的一个单一氨基酸突变，位于(682)YENPTY687基序的14个氨基酸末端，减少了Fe65蛋白家族成员与APP之间的相互作用，而APP与其他APP结合蛋白的磷酸酪氨酸相互作用域的相互作用不受该突变的影响：(Ii)APP在Thr-668处的磷酸化导致含有Fe65结合基序的细胞质结构域YENPTY的构象变化而减少了APP与Fe65的相互作用；Fe65的表达略微抑制了APP的成熟，减少了β-淀粉样蛋白(Aβ)的产生。APP的Thr-668位突变取消了Fc65对APP成熟的影响。该突变阻断了依赖于Fe65的Aβ产生的抑制，并导致在存在Fe65的情况下释放增加的Aβ水平。我们先前报道，在神经元APP的成熟过程中，该蛋白在Thr-668处被特异性磷酸化，并经历O-糖基化。目前的结果表明，O-糖基化的成熟A-PP在Thr-668处的磷酸化导致其胞浆结构域的构象变化，从而阻止Fe65与神经元的结合，并可能导致Aβ产生的改变。
Neuronal Fe65 is an adapter protein that interacts with the cytoplasmic domain of the beta -amyloid precursor protein (APP). Although the interaction has been reported to occur between the second phosphotyrosine interaction domain of Fe65 and the YENPTY motif in the cytoplasmic domain of APP, the regulatory mechanism and biological function of this interaction remain unknown. We report here that M a single amino acid mutation at the Thr-668 residue of APP695, located 14 amino acids toward the amino-terminal end from the (682) YENPTY687 motif, reduced the interaction between members of the Fe65 family of proteins and APP, whereas interaction of APP with the phosphotyrosine interaction domain of other APP binders such as X11-like and mammalian disabled-1 was not influenced by this mutation; (ii) the phosphorylation of APP at Thr-668 diminished the interaction of APP with Fe65 by causing a conformational change in the cytoplasmic domain that contains the Fe65-binding motif, YENPTY; and (iii) the expression of Fe65 slightly suppressed maturation of APP and decreased production of beta -amyloid (A beta). Mutation at Thr-668 of APP abolished the effect of Fc65 on APP maturation. This mutation blocked the Fe65-dependent suppression of A beta production and resulted in the release of increased levels of A beta in the presence of Fe65. We previously reported that during maturation of APP in neurons, the protein is specifically phosphorylated at Thr-668 and undergoes O-glycosylation. The present results suggest that the phosphorylation of O-glycosylated mature A-PP at Thr-668 causes a conformational change in its cytoplasmic domain that prevents binding of Fe65 in neurons and may lead to an alteration in the production of A beta.