Coordinated metabolism of alcadein and amyloid β-protein precursor regulates FE65-dependent gene transactivation
Coordinated metabolism of alcadein and amyloid β-protein precursor regulates FE65-dependent gene transactivation
复制标题
DOI：
10.1074/jbc.m401925200
复制
发表时间：
2004-06-04
影响因子：
4.8
通讯作者：
Suzuki, T
中科院分区：
文献类型：
--
作者：
Araki, Y;Miyagi, N;Suzuki, T
Alcadeins（Alcs）/calsyntenins和淀粉样β-蛋白前体（APP）通过经由其胞质结构域与X11 L（X11样蛋白）结合而在脑中彼此缔合。我们之前报道过这种APP-X11 L-Alc三重复合物的形成抑制了APP的代谢裂解。我们在这里表明Alc的代谢与APP的代谢显着相似。Alc经历初级裂解事件，释放其细胞外结构域。然后，Alc经历二次早老素依赖性γ裂解，导致淀粉样β蛋白样肽的分泌和胞内结构域片段（AlcICD）的释放。然而，当Alc是在三重复合物，它逃脱这些裂解，因为APP。我们还发现，AlcICD抑制的FE 65依赖的基因反式激活活性的APP胞内结构域片段，可能是因为AlcICD竞争与APP胞内结构域片段结合FE 65。我们提出，Alcs和APP在神经元中协同代谢，并且它们裂解的胞质片段不可避免地参与FE 65依赖的基因反式激活的调节。Alcs和APP代谢的任何失衡都可能影响FE 65依赖性基因的反式激活，这与淀粉样β蛋白分泌增加一起可能导致神经疾病。
The Alcadeins (Alcs)/calsyntenins and the amyloid beta-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent gamma-cleavage that leads to the secretion of the amyloid beta-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid beta-protein may contribute to neural disorders.