Defining the minimum substrate and charge recognition model of gamma-secretase
文献类型：期刊论文
| 作者 | Yan, Yan1,2,3,4; Xu, Ting-Hai1,2,3,4; Melcher, Karsten3,4; Xu, H. Eric2,3,4
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2017-10 |
| 卷号 | 38期号:10页码:1412-1424 |
| 关键词 | Alzheimer's disease amyloid beta (A beta) amyloid precursor protein (APP) C99, gamma-secretase minimum substrate Notch protein recognition model |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2017.35 |
| 文献子类 | Article |
| 英文摘要 | gamma-Secretase is an intramembrane aspartyl protease that cleaves the C99 fragment of amyloid precursor protein to generate extracellular A beta 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 gamma-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 gamma-secretase cleavage, and modulation of membrane PIP2 levels strongly affected gamma-secretase cleavage levels and the A beta(40)/A beta(42) ratio, providing support for the importance of the PIP2 interaction in cells. Together, these studies provide critically needed insight into substrate recognition by gamma-secretase. |
| WOS关键词 | ALZHEIMERS-DISEASE ; PRESENILIN/GAMMA-SECRETASE ; AMYLOID-BETA ; A-BETA ; COMPLEX ; NICASTRIN ; APH-1 ; NOTCH ; FRAGMENT ; RECEPTOR |
| 资助项目 | Van Andel Research Institute[00000000] ; National Natural Science Foundation of China[31300607] ; National Natural Science Foundation of China[31300245] ; National Natural Science Foundation of China[91217311] ; Ministry of Science and Technology grants of China[2012ZX09301001] ; Ministry of Science and Technology grants of China[2012CB910403] ; Ministry of Science and Technology grants of China[2013CB910600] ; Ministry of Science and Technology grants of China[XDB08020303] ; Ministry of Science and Technology grants of China[2013ZX09507001] ; Shanghai Science and Technology Committee[13ZR1447600] ; Shanghai Rising-Star Program[14QA1404300] ; National Institute of Health[DK071662] ; National Institute of Health[GM102545] ; National Institute of Health[GM104212] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6081563 |
| WOS记录号 | WOS:000412125600009 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272462]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Melcher, Karsten; Xu, H. Eric |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, Key Lab Receptor Res,VARI SIMM Ctr, Shanghai 201203, Peoples R China; 3.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 4.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA; |
| 推荐引用方式 GB/T 7714 | Yan, Yan,Xu, Ting-Hai,Melcher, Karsten,et al. Defining the minimum substrate and charge recognition model of gamma-secretase[J]. ACTA PHARMACOLOGICA SINICA,2017,38(10):1412-1424. |
| APA | Yan, Yan,Xu, Ting-Hai,Melcher, Karsten,&Xu, H. Eric.(2017).Defining the minimum substrate and charge recognition model of gamma-secretase.ACTA PHARMACOLOGICA SINICA,38(10),1412-1424. |
| MLA | Yan, Yan,et al."Defining the minimum substrate and charge recognition model of gamma-secretase".ACTA PHARMACOLOGICA SINICA 38.10(2017):1412-1424. |
入库方式： OAI收割
来源：上海药物研究所
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