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首页> 外文期刊>Nature >Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
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Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1

机译：指向活性位点的光活化γ-分泌酶抑制剂共价标记早老素1

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Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic peptides Aβ40 and Aβ42—the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of γ-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of Aβ42 (refs 4-6), the more amyloidogenic peptide; γ-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in trans-membrane segments of PS1 inactivates the ability of γ-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a γ-secretase cofactor, or helps to colocalize γ-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent γ-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of γ-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an activesite-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen.
机译：β和γ分泌酶对淀粉样前体蛋白（APP）的切割分别产生Aβ淀粉样蛋白生成肽Aβ40和Aβ42的氨基和羧基末端，Aβ40和Aβ42是阿尔茨海默病患者脑实质中淀粉样蛋白斑块的主要成分。有证据表明，跨膜跨膜蛋白早老素1和2（PS1和PS2）是γ分泌酶活性的重要决定因素：与早发家族性阿尔茨海默氏病相关的PS1和PS2突变会增加Aβ42的产生（参考文献4-6），具有更多淀粉样蛋白的肽；在源自缺乏PS1的小鼠胚胎的神经元培养物中，γ-分泌酶的活性降低；在PS1跨膜区段中两个保守的天冬氨酸的直接诱变会激活γ-分泌酶催化跨膜域内APP的加工能力。但是，PS1（与任何已知的天冬氨酰蛋白酶几乎没有同源性或没有同源性）本身是跨膜天冬氨酰蛋白酶还是γ-分泌酶辅因子，还是有助于将γ-分泌酶和APP共定位是未知的。在这里，我们报告了由有效的γ-分泌酶抑制剂对PS1（和PS2）进行光亲和性标记的方法，这些抑制剂被设计为充当针对天冬氨酰蛋白酶活性位点的过渡态类似物抑制剂。该观察结果表明PS1（和PS2）可能包含γ-分泌酶的活性位点。有趣的是，野生型PS1的完整单链形式没有被活性位点定向的光亲和探针标记，这表明完整的野生型PS1可能是天冬氨酰蛋白酶酶原。

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