Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.
Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.
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哺乳动物细胞中淀粉样前体蛋白和早老素之间的相互作用：对阿尔茨海默病发病机制的影响。
DOI：
10.1073/pnas.94.15.8208
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发表时间：
1997
影响因子：
11.1
通讯作者：
Selkoe,DJ
中科院分区：
文献类型：
--
作者：
Xia,W;Zhang,J;Perez,R;Koo,EH;Selkoe,DJ
早老素1（PS1）和早老素2（PS2）基因的突变增加了多种细胞系和转基因小鼠中高度淀粉样β蛋白（Aβ42）的42-残基形式的淀粉样蛋白的产生。为了阐明这种作用的分子机制，将野生型（wt）或突变型PS1和PS2基因稳定转染到表达内源性或转染的β-淀粉样前体蛋白（APP）的中国仓鼠卵巢细胞中。通过免疫沉淀/Western印迹分析，APP被一致地发现与PS1或PS2蛋白共免疫沉淀。几种不同的PS1，PS2或APP抗体沉淀PS-APP复合物，其可通过用APP或PS抗体印迹检测。重要的是，复合物的形成可以在未转染细胞的内源性蛋白质水平上检测到。在各种中国仓鼠卵巢细胞系中，PS抗体共沉淀的APP的量与APP和PS的表达水平成正比。APP-PS复合物也从人293和HS 683细胞中回收。APP的完全成熟是不需要的相互作用，大多数APP分子与PS复合的仅仅是N-糖基化。用布雷菲德菌素A处理细胞或在20°C孵育并不能阻断复合物的形成，这表明APP和PS之间的结合部分发生在内质网中。复合物的形成检测到野生型和突变型PS和APP蛋白。APP C-末端结构域的缺失并没有废除复合物的形成，这表明相互作用不会发生在蛋白质的胞质结构域。我们的研究结果表明，野生型和突变型PS1和PS2蛋白在活细胞中与APP形成复合物，强烈支持突变型PS与APP相互作用的方式，通过γ-分泌酶切割Aβ42增强后者的膜内蛋白水解的假设。
Mutations in thepresenilin 1(PS1) andpresenilin 2(PS2) genes increase the production of the highly amyloidogenic 42-residue form of amyloid β-protein (Aβ42) in a variety of cell lines and transgenic mice. To elucidate the molecular mechanism of this effect, wild-type (wt) or mutantPS1andPS2genes were stably transfected into Chinese hamster ovary cells expressing endogenous or transfected β-amyloid precursor protein (APP). By immunoprecipitation/Western blot analysis, APP was consistently found to coimmunoprecipitate with PS1 or PS2 proteins. Several distinct PS1, PS2, or APP antibodies precipitated PS–APP complexes that were detectable by blotting with either APP or PS antibodies. Importantly, complex formation could be detected at endogenous protein levels in nontransfected cells. In various Chinese hamster ovary cell lines, the amounts of APP coprecipitated by PS antibodies were proportional to the expression levels of both APP and PS. APP–PS complexes also were recovered from human 293 and HS683 cells. Full maturation of APP was not required for the interaction; most APP molecules complexed with PS were solely N-glycosylated. Treatment of cells with brefeldin A or incubation at 20°C did not block complex formation, suggesting that the association between APP and PS occurs in part in the endoplasmic reticulum. Complex formation was detected for both wt and mutant PS and APP proteins. Deletion of the APP C-terminal domain did not abrogate complex formation, suggesting that the interaction does not occur in the cytoplasmic domains of the proteins. Our results demonstrate that wt and mutant PS1 and PS2 proteins form complexes with APP in living cells, strongly supporting the hypothesis that mutant PS interacts with APP in a way that enhances the intramembranous proteolysis of the latter by a γ-secretase cleaving at Aβ42.
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阿尔茨海默病淀粉样蛋白前体蛋白。
DOI：
10.1016/s0021-9258(19)39590-0
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
T. Oltersdorf;P. Ward;T. Henriksson;E. Beattie;R. Neve;I. Lieberburg;L. Fritz
通讯作者：
L. Fritz
影响因子：
4.8
作者：
DeStrooper, B;Beullens, M;VanLeuven, F
通讯作者：
VanLeuven, F
影响因子：
4.2
作者：
MANN, DMA
通讯作者：
MANN, DMA
影响因子：
4.8
作者：
Vito, P;Wolozin, B;DAdamio, L
通讯作者：
DAdamio, L
膜蛋白之间的特异性跨细胞结合对阿尔茨海默病至关重要。
DOI：
10.1073/pnas.93.22.12575
发表时间：
1996
影响因子：
11.1
作者：
Dewji,NN;Singer,SJ
通讯作者：
Singer,SJ