Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones

Mol Cell. 2007 Oct 12;28(1):41-56. doi: 10.1016/j.molcel.2007.08.024.


GRP94, an essential endoplasmic reticulum chaperone, is required for the conformational maturation of proteins destined for cell-surface display or export. The extent to which GRP94 and its cytosolic paralog, Hsp90, share a common mechanism remains controversial. GRP94 has not been shown conclusively to hydrolyze ATP or bind cochaperones, and both activities, by contrast, result in conformational changes and N-terminal dimerization in Hsp90 that are critical for its function. Here, we report the 2.4 A crystal structure of mammalian GRP94 in complex with AMPPNP and ADP. The chaperone is conformationally insensitive to the identity of the bound nucleotide, adopting a "twisted V" conformation that precludes N-terminal domain dimerization. We also present conclusive evidence that GRP94 possesses ATPase activity. Our observations provide a structural explanation for GRP94's observed rate of ATP hydrolysis and suggest a model for the role of ATP binding and hydrolysis in the GRP94 chaperone cycle.

Publication types

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

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Adenylyl Imidodiphosphate / chemistry
  • Adenylyl Imidodiphosphate / metabolism
  • Animals
  • Crystallography, X-Ray
  • Dimerization
  • Dogs
  • HSP70 Heat-Shock Proteins / chemistry*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / chemistry*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Molecular Sequence Data
  • Protein Structure, Quaternary*
  • Protein Structure, Secondary*


  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • glucose-regulated proteins
  • Adenylyl Imidodiphosphate
  • Adenosine Diphosphate
  • Adenosine Triphosphate

Associated data

  • PDB/2O1T
  • PDB/2O1U
  • PDB/2O1V
  • PDB/2O1W