التفاصيل البيبلوغرافية
| العنوان: |
Stability of the Human Hsp90-p50Cdc37 Chaperone Complex against Nucleotides and Hsp90 Inhibitors, and the Influence of Phosphorylation by Casein Kinase 2 |
| المؤلفون: |
Sanne H. Olesen, Donna J. Ingles, Jin-Yi Zhu, Mathew P. Martin, Stephane Betzi, Gunda I. Georg, Joseph S. Tash, Ernst Schönbrunn |
| المصدر: |
Molecules, Vol 20, Iss 1, Pp 1643-1660 (2015) |
| بيانات النشر: |
MDPI AG, 2015. |
| سنة النشر: |
2015 |
| المجموعة: |
LCC:Organic chemistry |
| مصطلحات موضوعية: |
heat shock proteins, protein–protein interactions, protein phosphorylation, protein kinase, small molecule inhibitors, Organic chemistry, QD241-441 |
| الوصف: |
The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein–protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
1420-3049 |
| Relation: |
http://www.mdpi.com/1420-3049/20/1/1643; https://doaj.org/toc/1420-3049 |
| DOI: |
10.3390/molecules20011643 |
| URL الوصول: |
https://doaj.org/article/00296e6254394b5caf006653751a6a7c |
| رقم الانضمام: |
edsdoj.00296e6254394b5caf006653751a6a7c |
| قاعدة البيانات: |
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