GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42
GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42
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DOI：
10.1038/sj.emboj.7601616
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发表时间：
2007-03-21
期刊：
影响因子：
11.4
通讯作者：
Multhaup, Gerd
中科院分区：
文献类型：
--
作者：
Munter, Lisa-Marie;Voigt, Philipp;Multhaup, Gerd
β-和γ-分泌酶对淀粉样前体蛋白（APP）的加工导致产生不同长度的淀粉样β（A β）肽。特别是A β 42有助于阿尔茨海默病（AD）中的细胞毒性和淀粉样蛋白积累。然而，A β 42产生的确切分子机制仍不清楚。在这里，我们表明，APP跨膜序列（TMS）内的氨基酸基序GxxxG具有调节抗体种类的影响。在神经元细胞系统中，GxxxG基序的甘氨酸残基G29和G33的突变逐渐减弱TMS二聚化强度，特别是减少A β 42的形成，使A β 40的水平不受影响，但增加A β 38和更短的Ab种类。我们表明，甘氨酸残基G29和G33的TMS内的二聚化位点的一部分，但不损害APP胞外域的寡聚化。我们的结论是，γ-分泌酶裂解APP的底物TMS的二聚化强度密切相关。结果表明，APP TMS的二聚化是AD的危险因素，因为促进了A β 42的产生。
Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases leads to the generation of amyloid-beta (A beta) peptides with varying lengths. Particularly A beta 42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease ( AD). However, the precise molecular mechanism of A beta 42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Ab species produced. In a neuronal cell system, mutations of glycine residues G29 and G33 of the GxxxG motif gradually attenuate the TMS dimerization strength, specifically reduce the formation of A beta 42, leave the level of A beta 40 unaffected, but increase A beta 38 and shorter Ab species. We show that glycine residues G29 and G33 are part of a dimerization site within the TMS, but do not impair oligomerization of the APP ectodomain. We conclude that gamma-secretase cleavages of APP are intimately linked to the dimerization strength of the substrate TMS. The results demonstrate that dimerization of APP TMS is a risk factor for AD due to facilitating A beta 42 production.