Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase -: Common effects of Pen-2 N-terminal elongation and fenofibrate
Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase -: Common effects of Pen-2 N-terminal elongation and fenofibrate
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DOI：
10.1074/jbc.m611549200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Iwatsubo, Takeshi
中科院分区：
文献类型：
--
作者：
Isoo, Noriko;Sato, Chihiro;Iwatsubo, Takeshi
γ-分泌酶是一种非典型的γ-淀粉酰蛋白酶，其切割淀粉样β-前体蛋白以产生导致阿尔茨海默病的A β肽。γ-分泌酶是由早老素（PS）、nicastrin、Aph-1和Pen-2组成的多聚体膜蛋白复合物。Pen-2直接与PS的跨膜结构域4结合，并赋予γ-分泌酶蛋白水解活性，尽管其激活机制及其在催化中的作用仍不清楚。在这里，我们表明，在Pen-2的N末端添加氨基酸残基特别增加了A β 42的生成，A β 42是A β的更长和更易聚集的种类。Pen- 2的N末端延伸对A β 42产生的影响与氨基酸序列、表达系统和早老素种类无关。体外γ-分泌酶测定显示Pen-2直接影响γ-分泌酶的A β 42生成活性。Pen-2N末端的延长导致PS1的催化孔的管腔侧的水可及性的降低，其方式与A β 42升高γ-分泌酶调节剂非诺贝特所导致的方式相似，如通过取代的半胱氨酸可及性方法所确定的。这些数据表明A β 42过度产生的独特机制与通常由Pen-2和非诺贝特的N-末端延长引起的早老素催化孔的结构变化相关。
gamma-Secretase is an atypical aspartyl protease that cleaves amyloid beta-precursor protein to generate A beta peptides that are causative for Alzheimer disease. gamma-Secretase is a multimeric membrane protein complex composed of presenilin ( PS), nicastrin, Aph-1, and Pen-2. Pen-2 directly binds to transmembrane domain 4 of PS and confers proteolytic activity on gamma-secretase, although the mechanism of activation and its role in catalysis remain unknown. Here we show that an addition of amino acid residues to the N terminus of Pen-2 specifically increases the generation of A beta 42, the longer and more aggregable species of A beta. The effect of the N- terminal elongation of Pen- 2 on A beta 42 generation was independent of the amino acid sequences, the expression system and the presenilin species. In vitro gamma-secretase assay revealed that Pen-2 directly affects the A beta 42- generating activity of gamma-secretase. The elongation of Pen-2N terminus caused a reduction in the water accessibility of the luminal side of the catalytic pore of PS1 in a similar manner to that caused by an A beta 42- raising gamma-secretase modulator, fenofibrate, as determined by substituted cysteine accessibility method. These data suggest a unique mechanism of A beta 42 overproduction associated with structural changes in the catalytic pore of presenilins caused commonly by the N-terminal elongation of Pen-2 and fenofibrate.