Complex regulation of γ-secretase: from obligatory to modulatory subunits.
Complex regulation of γ-secretase: from obligatory to modulatory subunits.
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DOI：
10.3389/fnagi.2014.00342
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发表时间：
2014
影响因子：
4.8
通讯作者：
Li YM
中科院分区：
文献类型：
--
作者：
Gertsik N;Chiu D;Li YM
γ-分泌酶是一种四亚基、19 次跨膜酶，可裂解淀粉样前体蛋白 (APP)，催化淀粉样β (Aβ) 肽的形成，从而形成淀粉样斑块，从而导致阿尔茨海默病 (AD) 发病机制。 γ-分泌酶还可切割 Notch 以及许多其他 I 型跨膜底物。尽管其酶活性看似杂乱，但γ-分泌酶活性受到严格调控。这种调节是许多细胞实体的功能，包括但不限于必需的 γ-分泌酶亚基、非必需（调节）亚基和 γ-分泌酶底物。调节还通过一系列细胞事件来完成，例如早老素（γ-分泌酶的活性亚基）内切蛋白水解和缺氧。在这篇综述中，我们讨论了 γ-分泌酶是如何调节的，希望对这些机制的深入了解将有助于开发针对 γ-分泌酶相关疾病（如 AD 和 Notch 成瘾性癌症）的有效疗法。
γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aβ) peptides that form amyloid plaques, which contribute to Alzheimer’s disease (AD) pathogenesis. γ-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, γ-secretase activity is tightly regulated. This regulation is a function of many cellular entities, including but not limited to the essential γ-secretase subunits, nonessential (modulatory) subunits, and γ-secretase substrates. Regulation is also accomplished by an array of cellular events, such as presenilin (active subunit of γ-secretase) endoproteolysis and hypoxia. In this review we discuss how γ-secretase is regulated with the hope that an advanced understanding of these mechanisms will aid in the development of effective therapeutics for γ-secretase-associated diseases like AD and Notch-addicted cancer.
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