The X11α protein slows cellular amyloid precursor protein processing and reduces Aβ40 and Aβ42 secretion
The X11α protein slows cellular amyloid precursor protein processing and reduces Aβ40 and Aβ42 secretion
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DOI：
10.1074/jbc.273.24.14761
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发表时间：
1998-06-12
影响因子：
4.8
通讯作者：
Turner, RS
中科院分区：
文献类型：
--
作者：
Borg, JP;Yang, YN;Turner, RS
结构性淀粉样前体蛋白(APP)代谢导致可溶性APP(APP)和Aβ多肽的产生，包括Aβ40和Aβ42-阿尔茨海默病大脑淀粉样斑块的主要成分。X11的磷酸酪氨酸结合(PTB)结构域与APP的羧基末端含有YENPTY基序的多肽结合。我们已经克隆了全长的X11基因，现在被称为X11α。X11α与APP共表达导致相对较高的细胞APP水平和较少的APP，Aβ40和Aβ42在瞬时转染的HEK 293细胞的条件培养液中恢复。这些效应被APP(YENPTY基序中的Y682G)或X11α(PTB结构域中的F608V)的单个错义突变所削弱，从而减少了它们之间的相互作用，从而显示出特异性。通过与促进其淀粉样变性过程的瑞典突变APP(K595N/M596L)的共表达，X11α对Aβ40和Aβ42分泌的抑制作用被放大。脉冲追逐分析表明，X11α使APP的半衰期从接近2 h延长到接近4 h。在稳定表达APP的293细胞系中证实了X11α对APP细胞和APP回收率的影响。X11α的PTB结构域与APP的YENPTY基序多肽的特异性结合似乎减缓了细胞APP的处理，从而减少了其在HEK 293细胞条件培养液中的可溶性片段APP、Aβ40和Aβ42的恢复，X11α可能参与了APP在神经元中的运输和代谢，从而可能参与了正常衰老和阿尔茨海默病脑淀粉样蛋白的形成。
Constitutive amyloid precursor protein (APP) metabolism results in the generation of soluble APP (APPs) and A beta peptides, including A beta 40 and A beta 42-the major component of amyloid plaques in Alzheimer's disease brain. The phosphotyrosine binding (PTB) domain of X11 binds to a peptide containing a YENPTY motif found in the carboxyl terminus of APP. We have cloned the full-length X11 gene now referred to as X11 alpha. Coexpression of X11 alpha with APP results in comparatively greater levels of cellular APP and less APPs, A beta 40, and A beta 42 recovered in conditioned medium of transiently transfected HEK 293 cells. These effects are impaired by a single missense mutation of either APP (Y682G within the YENPTY motif) or X11 alpha (F608V within the PTB domain), which diminishes their interaction, thus demonstrating specificity. The inhibitory effect of X11 alpha on A beta 40 and A beta 42 secretion is amplified by coexpression with the Swedish mutation of APP (K595N/M596L), which promotes its amyloidogenic processing. Pulse-chase analysis demonstrates that X11 alpha prolongs the half-life of APP from similar to 2 h to similar to 4 h. The effects of X11 alpha on cellular APP and APPs recovery were confirmed in a 293 cell line stably transfected with APP. The specific binding of the PTB domain of X11 alpha to the YENPTY motif-containing peptide of APP appears to slow cellular APP processing and thus reduces recovery of its soluble fragments APPs, A beta 40, and A beta 42 in conditioned medium of transfected HEK 293 cells, X11 alpha may be involved in APP trafficking and metabolism in neurons and thus may be implicated in amyloidogenesis in normal aging and Alzheimer's disease brain.