Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2952-7. doi: 10.1073/pnas.1516167113. Epub 2016 Feb 29.


Heat-shock protein of 90 kDa (Hsp90) is an essential molecular chaperone that adopts different 3D structures associated with distinct nucleotide states: a wide-open, V-shaped dimer in the apo state and a twisted, N-terminally closed dimer with ATP. Although the N domain is known to mediate ATP binding, how Hsp90 senses the bound nucleotide and facilitates dimer closure remains unclear. Here we present atomic structures of human mitochondrial Hsp90N (TRAP1N) and a composite model of intact TRAP1 revealing a previously unobserved coiled-coil dimer conformation that may precede dimer closure and is conserved in intact TRAP1 in solution. Our structure suggests that TRAP1 normally exists in an autoinhibited state with the ATP lid bound to the nucleotide-binding pocket. ATP binding displaces the ATP lid that signals the cis-bound ATP status to the neighboring subunit in a highly cooperative manner compatible with the coiled-coil intermediate state. We propose that TRAP1 is a ligand-activated molecular chaperone, which couples ATP binding to dramatic changes in local structure required for protein folding.

Keywords: Hsp90; TRAP1; molecular chaperone.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism*
  • Allosteric Regulation
  • Allosteric Site
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • HSP70 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Mitochondria / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Rabbits
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid


  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Recombinant Fusion Proteins
  • TRAP1 protein, human
  • Adenosine Triphosphate

Associated data

  • PDB/5F3K
  • PDB/5F5R