A Basic Amino Acid in the Cytoplasmic Domain of Alzheimer’s β-Amyloid Precursor Protein (APP) Is Essential for Cleavage of APP at the α-Site*
A Basic Amino Acid in the Cytoplasmic Domain of Alzheimer’s β-Amyloid Precursor Protein (APP) Is Essential for Cleavage of APP at the α-Site*
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阿尔茨海默病 β-淀粉样前体蛋白 (APP) 细胞质结构域中的碱性氨基酸对于 APP 在 α 位点的裂解至关重要*
DOI：
10.1074/jbc.273.30.19304
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Toshiharu Suzuki
中科院分区：
文献类型：
--
作者：
S. Tomita;Y. Kirino;Toshiharu Suzuki
在阿尔茨海默病(AD)中，β-淀粉样多肽(A-β)被认为是由于β-淀粉样前体蛋白(APP)代谢异常而产生的。我们报道，APP胞质结构域包含一个新的和重要的APP代谢信号。一个氨基酸突变使APP770的第747位(对应于APP695的第672位)的精氨酸变为非碱性氨基酸，大大增加了细胞内β位点(S)切割的APP羧基末端片段(β)的产量，但并未导致Aβ40和Aβ42的分泌增加。这不是由于缺乏β分泌酶而导致的简单的细胞内γ积聚所致。该突变体APP产生的CTFβ的生成和降解效率与野生型APP产生的CTFβ相同。这一结果表明，CTFβ数量的增加并不总是像先前对APP家族性AD突变的研究所表明的那样，产生更多的Aβ。这些发现表明，APP携带这一碱性氨基酸的替代突变可能通过另一种蛋白质分泌途径进行代谢。虽然这些结果还没有完全阐明为什么突变型APP产生的CTFβ逃脱了γ分泌酶的后续切割，但对这个突变型APP的处理途径的分析应该可以为散发性AD的发病机制提供深入的认识。
In Alzheimer’s disease (AD), the β-amyloid peptide (Aβ) is thought to be produced as a result of the aberrant metabolism of β-amyloid precursor protein (APP). We report that the APP cytoplasmic domain contains a novel and important signal for APP metabolism. A single amino acid mutation that changed arginine at amino acid 747 of APP770 (corresponding to position 672 of APP695) to a non-basic amino acid greatly increased the production of intracellular APP carboxyl-terminal fragment(s) cleaved at β-site(s) (CTFβ), but did not result in increased secretion of Aβ40 and Aβ42. This was not due to a simple intracellular accumulation of CTFβ resulting from a lack of γ-secretase. CTFβ derived from this mutant APP was generated and degraded as efficiently as CTFβ derived from wild-type APP. This result indicates that the increase in the quantity of CTFβ does not always give rise to more Aβ production, as was previously suggested by studies of a familial AD mutation of APP. These findings suggest that APP carrying the substitution mutation at this basic amino acid may be metabolized by another protein secretory pathway. Although these results have not completely elucidated why CTFβ derived from the mutant APP escapes from subsequent cleavage by γ-secretase, analysis of the processing pathway of this mutant APP should provide insights into the pathogenesis of the sporadic type of AD.
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与家族性阿尔茨海默病基因座相关的突变导致淀粉样β-蛋白前体的替代加工。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Haass,C;Hung,AY;Selkoe,DJ;Teplow,DB
通讯作者：
Teplow,DB
DOI：
10.1073/pnas.91.25.11993
发表时间：
1994-12-06
影响因子：
11.1
作者：
CITRON, M;VIGOPELFREY, C;SELKOE, DJ
通讯作者：
SELKOE, DJ
DOI：
10.1073/pnas.87.15.6003
发表时间：
1990-08-01
影响因子：
11.1
作者：
BUXBAUM, JD;GANDY, SE;GREENGARD, P
通讯作者：
GREENGARD, P
影响因子：
56.9
作者：
SUZUKI, N;CHEUNG, TT;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
影响因子：
56.9
作者：
MURRELL, J;FARLOW, M;BENSON, MD
通讯作者：
BENSON, MD