Localization of mature neprilysin in lipid rafts.
Localization of mature neprilysin in lipid rafts.
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成熟脑啡肽酶在脂筏中的定位。
DOI：
10.1002/jnr.22796
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Ishiura S.
中科院分区：
文献类型：
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作者：
Sato K;Tanabe C;Yonemura Y;Watahiki H;Zhao Y;Yagishita S;Ebina M;Suo S;Futai E;Murata M;Ishiura S.
阿尔茨海默病（AD）的特征是由淀粉样蛋白β肽（Aβ）积累引起的老年斑。据报道，Aβ的生成和积累发生在膜微域，称为脂筏，富含胆固醇和鞘糖脂。此外，胆固醇代谢的消融与阿尔茨海默病有关。Neprilysin （NEP）是一种中性内肽酶，是大脑中主要的a β -降解酶之一。活化NEP是一个可能的治疗靶点。然而，目前尚不清楚NEP的活性是否受其与脂筏的关联所调节。在这里，我们发现只有在高尔基体中被糖基化的成熟形式的NEP存在于脂筏中，在脂筏中它与磷脂酰丝氨酸直接相关。此外，NEP在脂筏中的定位通过其二聚化而增强，如NEP E403C二聚化突变体所示。然而，通过体外肽水解评估，成熟形式的NEP的蛋白酶活性在脂筏和非脂筏之间没有差异。我们得出结论，胆固醇和其他脂质调节成熟NEP向脂筏的定位，在脂筏中底物Aβ积累，但不调节NEP的蛋白酶活性。©2011 Wiley期刊公司
Alzheimer's disease (AD) is characterized by senile plaques caused by amyloid‐β peptide (Aβ) accumulation. It has been reported that Aβ generation and accumulation occur in membrane microdomains, calledlipid rafts, which are enriched in cholesterol and glycosphingolipids. Moreover, the ablation of cholesterol metabolism has been implicated in AD. Neprilysin (NEP), a neutral endopeptidase, is one of the major Aβ‐degrading enzymes in the brain. Activation of NEP is a possible therapeutic target. However, it remains unknown whether the activity of NEP is regulated by its association with lipid rafts. Here we show that only the mature form of NEP, which has been glycosylated in the Golgi, exists in lipid rafts, where it is directly associated with phosphatidylserine. Moreover, the localization of NEP in lipid rafts is enhanced by its dimerization, as shown using the NEP E403C homodimerization mutant. However, the protease activities of the mature form of NEP, as assessed by in vitro peptide hydrolysis, did not differ between lipid rafts and nonlipid rafts. We conclude that cholesterol and other lipids regulate the localization of mature NEP to lipid rafts, where the substrate Aβ accumulates but does not modulate the protease activity of NEP. © 2011 Wiley Periodicals, Inc.