Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the A beta 42/A beta 40 ratio
文献类型：期刊论文
| 作者 | Xu, Ting-Hai1,2,3,4; Yan, Yan1,2,3,4; Kang, Yanyong1,4; Jiang, Yi3 ; Melcher, Karsten1,4; Xu, H. Eric1,3,4
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| 刊名 | CELL DISCOVERY
 |
| 出版日期 | 2016-08-23 |
| 卷号 | 2 |
| 关键词 | Alzheimer's disease C99 gamma-secretase familial Alzheimer disease (FAD)-linked mutations epsilon-cleavage assay |
| ISSN号 | 2056-5968 |
| DOI | 10.1038/celldisc.2016.26 |
| 文献子类 | Article |
| 英文摘要 | Mutations in the amyloid precursor protein (APP) gene and the aberrant cleavage of APP by gamma-secretase are associated with Alzheimer's disease (AD). Here we have developed a simple and sensitive cell-based assay to detect APP cleavage by gamma-secretase. Unexpectedly, most familial AD (FAD)-linked APP mutations make APP partially resistant to gamma-secretase. Mutations that alter residues N terminal to the gamma-secretase cleavage site A beta 42 have subtle effects on cleavage efficiency and cleavage-site selectivity. In contrast, mutations that alter residues C terminal to the A beta 42 site reduce cleavage efficiency and dramatically shift cleavage-site specificity toward the aggregation-prone A beta 42. Moreover, mutations that remove positive charge at residue 53 greatly reduce the APP cleavage by gamma-secretase. These results suggest a model of gamma-secretase substrate recognition, in which the APP region C terminal to the A beta 42 site and the positively charged residue at position 53 are the primary determinants for substrate binding and cleavage-site selectivity. We further demonstrate that this model can be extended to gamma-secretase processing of notch receptors, a family of highly conserved cell-surface signaling proteins. |
| WOS关键词 | A-BETA PRODUCTION ; TRANSMEMBRANE DOMAIN ; MOLECULAR PATHOLOGY ; PEPTIDE PRODUCTION ; STRUCTURAL BASIS ; ZETA-CLEAVAGE ; PRESENILIN ; HYPOTHESIS ; NICASTRIN ; COMPLEX |
| 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[2012ZX09301001] ; Ministry of Science and Technology[2012CB910403] ; Ministry of Science and Technology[2013CB910600] ; Ministry of Science and Technology[XDB08020303] ; Ministry of Science and Technology[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 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000414849700001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275924]  |
| 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.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA; 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, Key Lab Receptor Res,VARI SIMM Ctr, Shanghai, Peoples R China; 4.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; |
| 推荐引用方式 GB/T 7714 | Xu, Ting-Hai,Yan, Yan,Kang, Yanyong,et al. Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the A beta 42/A beta 40 ratio[J]. CELL DISCOVERY,2016,2. |
| APA | Xu, Ting-Hai,Yan, Yan,Kang, Yanyong,Jiang, Yi,Melcher, Karsten,&Xu, H. Eric.(2016).Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the A beta 42/A beta 40 ratio.CELL DISCOVERY,2. |
| MLA | Xu, Ting-Hai,et al."Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the A beta 42/A beta 40 ratio".CELL DISCOVERY 2(2016). |
入库方式： OAI收割
来源：上海药物研究所
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