definingtheminimumsubstrateandchargerecognitionmodelofgammasecretase
文献类型：期刊论文
| 作者 | Yan Yan1; Xu Tinghai1; Melcher Karsten2; Xu H Eric1 |
| 刊名 | actapharmacologicasinica
 |
| 出版日期 | 2017 |
| 卷号 | 038期号:010页码:1412 |
| 关键词 | 识别模型 分泌酶 基板 淀粉样前体蛋白 天冬氨酸蛋白酶 定义 阿尔茨海默病 氨基酸序列 |
| ISSN号 | 1671-4083 |
| 英文摘要 | γ-Secretase is an intramembrane aspartyl protease that cleaves the C99 fragment of amyloid precursor protein to generate extracellular Aβ peptides. These peptides can oligomerize and aggregate to form amyloid plaques, processes that are widely believed to be causal for Alzheimer＇s disease. In spite of this critical function, it remains unknown how γ-secretase recognizes C99 and its other substrates, including Notch.In this study we determined E22-K55 as the minimal C99 fragment that was sufficient and required for initial cleavage. Within this fragment, we identified four determinants： （i） a transferable extracellular determinant that differed between C99 and Notch, and which included negative charge in the case of C99, （ii） the amino acid sequence of the C-terminal half of the transmembrane helix, （iii） an invariant lysine or arginine at the intracellular membrane border, and （iv） a positive charge cluster that included the invariant lysine/arginine. We demonstrated that the charge clusters of C99 and Notch receptors could directly bind phosphatidylinositol 4,5-bisphosphate （PIP2）. The PIP2-binding cluster was required for γ-secretase cleavage, and modulation of membrane PIP2 levels strongly affected γ-secretase cleavage levels and the Aβ40/Aβ42 ratio, providing support for the importance of the PIP2 interaction in cells. Together, these studies provide critically needed insight into substrate recognition by γ-secretase. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/286842]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.中国科学院上海药物研究所 2.Laboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute |
| 推荐引用方式 GB/T 7714 | Yan Yan,Xu Tinghai,Melcher Karsten,et al. definingtheminimumsubstrateandchargerecognitionmodelofgammasecretase[J]. actapharmacologicasinica,2017,038(010):1412. |
| APA | Yan Yan,Xu Tinghai,Melcher Karsten,&Xu H Eric.(2017).definingtheminimumsubstrateandchargerecognitionmodelofgammasecretase.actapharmacologicasinica,038(010),1412. |
| MLA | Yan Yan,et al."definingtheminimumsubstrateandchargerecognitionmodelofgammasecretase".actapharmacologicasinica 038.010(2017):1412. |
入库方式： OAI收割
来源：上海药物研究所
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