Modulation of Amyloid Precursor Protein Metabolism by X11α/Mint-1
Modulation of Amyloid Precursor Protein Metabolism by X11α/Mint-1
复制标题
X11α/Mint-1 对淀粉样前体蛋白代谢的调节
DOI：
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复制
发表时间：
2000
影响因子：
4.8
通讯作者：
R. Turner
中科院分区：
文献类型：
--
作者：
H. T. Mueller;J. Borg;B. Margolis;R. Turner
淀粉样前体蛋白（APP）代谢的调节在阿尔茨海默病的发病机制中起着关键作用。磷酸酪氨酸结合/蛋白相互作用（PTB/PI）结构域与APP胞质羧基末端的YENPTY序列结合，这种相互作用延长APP的半衰期，抑制a β40和a β42的分泌。X11α/Mint-1具有多个蛋白相互作用结构域，一个Munc-18相互作用结构域（MID）、一个Cask/Lin-2相互作用结构域（CID）、一个PTB/PI结构域和两个PDZ结构域。这些X11α蛋白相互作用域可能调节其在APP加工中的作用。为了验证这一假设，我们通过瞬时共转染HEK 293细胞，分析了X11α对APP695瑞典（K595N/M596L） （APPsw）代谢的影响：1)X11α （X11α-wt, n - mid - sid - pdb - pdz - pdz - c), 2)氨基末端缺失（X11α-ΔN, pdb - pdz - pdz）， 3）羧基末端缺失（X11α-ΔPDZ, mid - sid -PTB），或4)两个末端缺失（PTB域，PTB）。X11α的羧基端是细胞中APPsw稳定所必需的。相比之下，X11α的氨基端是刺激app分泌的必要条件。X11α、X11α-ΔN和X11α- ptb是Aβ40和Aβ42分泌的有效抑制剂，而X11α-ΔPDZ则不是。这些结果表明，X11α的其他蛋白相互作用域调节APP代谢的各个方面。
Modulation of amyloid precursor protein (APP) metabolism plays a pivotal role in the pathogenesis of Alzheimer's disease. The phosphotyrosine-binding/protein interaction (PTB/PI) domain of X11α, a neuronal cytosolic adaptor protein, binds to the YENPTY sequence in the cytoplasmic carboxyl terminus of APP. This interaction prolongs the half-life of APP and inhibits Aβ40 and Aβ42 secretion. X11α/Mint-1 has multiple protein-protein interaction domains, a Munc-18 interaction domain (MID), a Cask/Lin-2 interaction domain (CID), a PTB/PI domain, and two PDZ domains. These X11α protein interaction domains may modulate its effect on APP processing. To test this hypothesis, we performed a deletion analysis of X11α effects on metabolism of APP695 Swedish (K595N/M596L) (APPsw) by transient cotransfection of HEK 293 cells with: 1) X11α (X11α-wt, N-MID-CID-PTB-PDZ-PDZ-C), 2) amino-terminal deletion (X11α-ΔN, PTB-PDZ-PDZ), 3) carboxyl-terminal deletion (X11α-ΔPDZ, MID-CID-PTB), or 4) deletion of both termini (PTB domain only, PTB). The carboxyl terminus of X11α was required for stabilization of APPsw in cells. In contrast, the amino terminus of X11α was required to stimulate APPs secretion. X11α, X11α-ΔN, and X11α-PTB, but not X11α-ΔPDZ, were effective inhibitors of Aβ40 and Aβ42 secretion. These results suggest that additional protein interaction domains of X11α modulate various aspects of APP metabolism.
影响因子：
56.9
作者：
Walhout, AJM;Sordella, R;Vidal, M
通讯作者：
Vidal, M
DOI：
10.1073/pnas.97.16.9287
发表时间：
2000-08-01
影响因子：
11.1
作者：
Feng, J;Yan, Z;Greengard, P
通讯作者：
Greengard, P
影响因子：
56.9
作者：
KAVANAUGH, WM;WILLIAMS, LT
通讯作者：
WILLIAMS, LT