Ligand-induced conformational shift in the N-terminal domain of GRP94, an Hsp90 chaperone.
GRP94 is the endoplasmic reticulum paralog of cytoplasmic Hsp90. Models of Hsp90 action posit an ATP-dependent conformational switch in the N-terminal ligand regulatory domain of the chaperone. However, crystal structures of the isolated N-domain of Hsp90 in complex with a variety of ligands have yet to demonstrate such a conformational change. We have determined the structure of the N-domain of GRP94 in complex with ATP, ADP, and AMP. Compared with the N-ethylcarboxamidoadenosine and radicicol-bound forms, these structures reveal a large conformational rearrangement in the protein. The nucleotide-bound form exposes new surfaces that interact to form a biochemically plausible dimer that is reminiscent of those seen in structures of MutL and DNA gyrase. Weak ATP binding and a conformational change in response to ligand identity are distinctive mechanistic features of GRP94 and suggest a model for how GRP94 functions in the absence of co-chaperones and ATP hydrolysis.
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
Robert M
RM
Immormino
D Eric
DE
Dollins
Paul L
PL
Shaffer
Karen L
KL
Soldano
Melissa A
MA
Walker
Daniel T
DT
Gewirth
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D003460:Crystallization; D027081:DNA Gyrase / Q000737:chemistry; D004285:Dogs; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D011487:Protein Conformation
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D000255:Adenosine Triphosphate; D027081:DNA Gyrase