Novel cadherin-related membrane proteins, alcadeins, enhance the X11-like protein-mediated stabilization of amyloid β-protein precursor metabolism
Novel cadherin-related membrane proteins, alcadeins, enhance the X11-like protein-mediated stabilization of amyloid β-protein precursor metabolism
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DOI：
10.1074/jbc.m306024200
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发表时间：
2003-12-05
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;Tomita, S;Suzuki, T
先前我们发现x11样蛋白（X11L）与淀粉样β蛋白前体（APP）相关。X11L稳定APP代谢，抑制淀粉样β蛋白（Abeta）的分泌，而淀粉样β蛋白是阿尔茨海默病（AD）的致病因子。在这里，我们发现Alcadein (Alc)，一个新的膜蛋白家族，包含钙粘蛋白基序，最初报道为钙syntenins，也与X11L相互作用。Alc在大脑中含量丰富，并且与X11L发生在相同的大脑区域。X11L可以同时与APP和Alc结合，在脑内形成三方复合物。三方复合物稳定了细胞内APP代谢，并增强了x11l介导的抑制β分泌的作用，这是由于细胞内APP成熟的延迟。X11L和Alc还与C99形成了另一个配合物，C99是APP的羧基末端片段，在β位点被切割（ctfβ）。Alc的形成。X11L。C99复合物抑制C99与早老素的相互作用，从而强烈抑制C99的γ -裂解。在AD患者大脑中，Alc和APP特别集中在老年斑的营养不良神经突中。缺乏x11l介导的Alc与APP和/或ctfβ之间的相互作用可增强β的产生，这可能与AD的发生或进展有关。
Previously we found that X11-like protein (X11L) associates with amyloid beta-protein precursor (APP). X11L stabilizes APP metabolism and suppresses the secretion of the amyloid beta-protein (Abeta) that are the pathogenic agents of Alzheimer's disease (AD). Here we found that Alcadein (Alc), a novel membrane protein family that contains cadherin motifs and originally reported as calsyntenins, also interacted with X11L. Alc was abundant in the brain and occurred in the same areas of the brain as X11L. X11L could simultaneously associate with APP and Alc, resulting in the formation of a tripartite complex in brain. The tripartite complex stabilized intracellular APP metabolism and enhanced the X11L-mediated suppression of Abeta secretion that is due to the retardation of intracellular APP maturation. X11L and Alc also formed another complex with C99, a carboxyl-terminal fragment of APP cleaved at the beta-site (CTFbeta). The formation of the Alc . X11L . C99 complex inhibited the interaction of C99 with presenilin, which strongly suppressed the gamma-cleavage of C99. In AD patient brains, Alc and APP were particularly colocalized in dystrophic neurites in senile plaques. Deficiencies in the X11L-mediated interaction between Alc and APP and/or CTFbeta enhanced the production of Abeta, which may be related to the development or progression of AD.