Identification of caspases that cleave presenilin-1 and presenilin-2 - Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases

被引:52
作者
van de Craen, M
de Jonghe, C
van den Brande, I
Declercq, W
van Gassen, G
van Criekinge, W
Vanderhoeven, I
Fiers, W
van Broeckhoven, C
Hendriks, L
Vandenabeele, P
机构
[1] Flanders Interuniv Inst Biotechnol, Dept Mol Biol, B-9000 Ghent, Belgium
[2] State Univ Ghent, B-9000 Ghent, Belgium
[3] Flanders Interuniv Inst Biotechnol, Born Bunge Fdn, Neurogenet Lab, B-2610 Wilrijk, Belgium
[4] Univ Instelling Antwerp, B-2610 Wilrijk, Belgium
关键词
Alzheimer's disease; caspase; cleavage; presenilin; substrate;
D O I
10.1016/S0014-5793(99)00108-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in the presenilin (PS) genes PS1 and PS2 are involved in Alzheimer's disease (AD), Recently, apoptosis-associated cleavage of PS proteins was identified. Here we demonstrate that PS1 as well as PS2 are substrates for different members of the caspase protein family. Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD(341). A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341 Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329 Caspase-8 and -3 exhibited the highest proteolytic activity on both PS1 and PS2, PSI and PS2 were not hydrolyzed by caspase-2 and PS2 also not by caspase-11, None of five missense mutations affected the sensitivity of PS1 to caspase-mediated cleavage. This suggests that AD pathogenesis associated with PS1 missense mutations cannot be explained by a change in caspase-dependent processing. (C) 1999 Federation of European Biochemical Societies.
引用
收藏
页码:149 / 154
页数:6
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