Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs
Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs
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DOI：
10.1074/jbc.m707142200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Octave, Jean-Noel
中科院分区：
文献类型：
--
作者：
Kienlen-Campard, Pascal;Tasiaux, Bernadette;Octave, Jean-Noel
β-淀粉样肽(Aβ)是阿尔茨海默病患者大脑中发现的老年斑的淀粉样蛋白核心的主要成分。β蛋白是由淀粉样前体蛋白(APP)被β-和伽马分泌酶连续裂解而产生的。APP被γ-分泌酶切割后还产生APP胞内C-末端结构域(AICD)，可能参与基因转录调控。APP在其邻近膜和跨膜区含有三个Gly-XXX-Gly(GXXXG)基序。已知这些基序通过TM序列的紧密重叠来促进二聚化。我们证明，在GXXXG基序中，亮氨酸或异亮氨酸成对替换甘氨酸，而不是丙氨酸，导致Aβ40和Aβ42分泌急剧减少。突变型APP的β-裂解不受抑制，而Aβ的分泌减少是由于抑制了γ-裂解。预计突变的APP的伽马裂解减少是由于其二聚化被抑制所致。令人惊讶的是，GXXXG基序的突变实际上增强了APP C末端片段的二聚化，可能是通过不同的TMα-螺旋界面。TM APP C-末端结构域的二聚化增加并不影响AICD的产生。
The beta-amyloid peptide (A beta) is the major constituent of the amyloid core of senile plaques found in the brain of patients with Alzheimer disease. A beta is produced by the sequential cleavage of the amyloid precursor protein (APP) by beta-and gamma-secretases. Cleavage of APP by gamma-secretase also generates the APP intracellular C-terminal domain (AICD) peptide, which might be involved in regulation of gene transcription. APP contains three Gly-XXX-Gly (GXXXG) motifs in its jux-tamembrane and transmembrane (TM) regions. Such motifs are known to promote dimerization via close apposition of TM sequences. We demonstrate that pairwise replacement of glycines by leucines or isoleucines, but not alanines, in a GXXXG motif led to a drastic reduction of A beta 40 and A beta 42 secretion. beta-Cleavage of mutant APP was not inhibited, and reduction of A beta secretion resulted from inhibition of gamma-cleavage. It was anticipated that decreased gamma-cleavage of mutant APP would result from inhibition of its dimerization. Surprisingly, mutations of the GXXXG motif actually enhanced dimerization of the APP C-terminal fragments, possibly via a different TM alpha-helical interface. Increased dimerization of the TM APP C-terminal domain did not affect AICD production.