2. Academic Validation
  3. A dynamic view of ATP-coupled functioning cycle of Hsp90 N-terminal domain

A dynamic view of ATP-coupled functioning cycle of Hsp90 N-terminal domain

  • Sci Rep. 2015 Apr 13;5:9542. doi: 10.1038/srep09542.
Huaqun Zhang 1,  Chen Zhou 1,  Wuyan Chen 2,  Yechun Xu 2,  Yanhong Shi 1,  Yi Wen 1,  Naixia Zhang 3
Affiliations

Affiliations

  • 1 Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 2 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 3 1] Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China [2] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
PMID: 25867902 DOI: 10.1038/srep09542
Abstract

Heat-shock protein 90 (HSP90) is one of the most important chaperones involved in multiple cellular processes. The chaperoning function of HSP90 is intimately coupled to the ATPase activity presented by its N-terminal domain. However, the molecular mechanism for the ATP-dependent working cycle of HSP90 is still not fully understood. In this study, we use NMR techniques to investigate the structural characteristics and dynamic behaviors of HSP90 N-terminal domain in its free and AMPPCP (ATP analogue) or ADP-bound states. We demonstrated that although AMPPCP and ADP bind to almost the same region of HSP90, significantly different effects on the dynamics behaviors of the key structural elements were observed. AMPPCP binding favors the formation of the active homodimer of HSP90 by enhancing the slow-motion featured conformational exchanges of those residues (A117-A141) within the lid segment (A111-G135) and around region, while ADP binding keeps HSP90 staying at the inactive state by increasing the conformational rigidity of the lid segment and around region. Based on our findings, a dynamic working model for the ATP-dependent functioning cycle of HSP90 was proposed.

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