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DOI | 10.1038/s41467-019-08348-1 |
Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex | |
Oroz, Javier1,8; Chang, Bliss J.2; Wysoczanski, Piotr1,2; Lee, Chung-Tien3; Perez-Lara, Angel4; Chakraborty, Pijush1; Hofele, Romina V.3; Baker, Jeremy D.5; Blair, Laura J.5; Biernat, Jacek6; Urlaub, Henning3,7; Mandelkow, Eckhard6; Dickey, Chad A.5; Zweckstetter, Markus1,2 | |
2019-02-14 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | Germany; USA; Spain |
英文摘要 | The molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-length Hsp90 in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer's disease-related protein Tau. We reveal that the FKBP51/Hsp90 complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp90 dimer resulting in decreased Hsp90 ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau's proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. Our study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000448807000003 |
WOS关键词 | INTRINSICALLY DISORDERED PROTEINS ; MOLECULAR-WEIGHT PROTEINS ; HEAT-SHOCK-PROTEIN ; FUNCTIONAL-ANALYSIS ; ESCHERICHIA-COLI ; ATP HYDROLYSIS ; METHYL-GROUPS ; HSP90 ; TAU ; NMR |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204222 |
专题 | 资源环境科学 |
作者单位 | 1.German Ctr Neurodegenerat Dis DZNE, Von Siebold Str 3a, D-37075 Gottingen, Germany; 2.Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, Fassberg 11, D-37077 Gottingen, Germany; 3.Max Planck Inst Biophys Chem, Bioanalyt Mass Spectrometry, Fassberg 11, D-37077 Gottingen, Germany; 4.Max Planck Inst Biophys Chem, Dept Neurobiol, Fassberg 11, D-37077 Gottingen, Germany; 5.Univ S Florida, USF Hlth Byrd Alzheimers Inst, Morsani Coll Med, Dept Mol Med, Tampa, FL 33613 USA; 6.CAESAR Res Ctr, DZNE, Ludwig Erhard Alle 2, D-53175 Bonn, Germany; 7.Univ Med Ctr, Inst Clin Chem, Bioanalyt Grp, Robert Koch Str 40, D-37075 Gottingen, Germany; 8.CSIC, IQFR, Inst Quim Fis Rocasolano, Serrano 119, Madrid 28006, Spain |
推荐引用方式 GB/T 7714 | Oroz, Javier,Chang, Bliss J.,Wysoczanski, Piotr,et al. Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex[J]. NATURE COMMUNICATIONS,2019,9. |
APA | Oroz, Javier.,Chang, Bliss J..,Wysoczanski, Piotr.,Lee, Chung-Tien.,Perez-Lara, Angel.,...&Zweckstetter, Markus.(2019).Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.NATURE COMMUNICATIONS,9. |
MLA | Oroz, Javier,et al."Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex".NATURE COMMUNICATIONS 9(2019). |
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