Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator
Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator
复制标题
DOI：
10.1073/pnas.1402171111
复制
发表时间：
2014-07-22
影响因子：
11.1
通讯作者：
Iwatsubo, Takeshi
中科院分区：
文献类型：
--
作者：
Takeo, Koji;Tanimura, Shun;Iwatsubo, Takeshi
γ-分泌酶是一种膜内裂解酶，负责产生淀粉样β蛋白(Aβ)多肽。最近，一系列被称为分泌酶调节剂(GSM)的化合物被证明可以降低长毒性Aβ物种(即Aβ42)的水平，同时伴随着短Aβ物种产量的增加。在这项研究中，我们证明了苯咪唑型GSM变构诱导-分泌酶催化部位的构象变化以增强蛋白分解活性。利用光亲和标记技术进行的分析和系统的突变研究表明，苯咪唑型GSM的靶标是早老素(PS)的N-末端片段中一个以前未被鉴定的胞外结合口袋。总之，我们为苯咪唑型GSM的作用机制提供了一个模型，在该模型中，PS管腔一侧的结合诱导分泌酶催化中心的构象变化，以调节Aβ的产生。
gamma-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-beta (A beta) peptides. Recently, a series of compounds called.-secretase modulators (GSMs) has been shown to decrease the levels of long toxic A beta species (i.e., A beta 42), with a concomitant elevation of the production of shorter A beta species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of.-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of.-secretase to modulate A beta production.