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

Sci Rep. 2015 Apr 13:5:9542. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • HSP90 Heat-Shock Proteins / chemistry*
  • HSP90 Heat-Shock Proteins / metabolism
  • Models, Biological
  • Models, Molecular*
  • Molecular Conformation
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Thermodynamics

Substances

  • HSP90 Heat-Shock Proteins
  • 5'-adenylyl (beta,gamma-methylene)diphosphonate
  • Adenosine Diphosphate
  • Adenosine Triphosphate