Structures of GRP94-Nucleotide Complexes Reveal Mechanistic Differences Between the Hsp90 Chaperones

Journal Article · Tue Jun 02 04:00:00 EDT 2009 · Mol. Cell 28:41,2007

OSTI ID:953977

Dollins, D E; Warren, J J; Immormino, R M; Gewirth, D T

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 {angstrom} 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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953977
• Report Number(s): SLAC-REPRINT-2009-415
• Journal Information: Mol. Cell 28:41,2007, Journal Name: Mol. Cell 28:41,2007 Journal Issue: 1 Vol. 28; ISSN 1097-2765
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ADP
ATP
COMPLEXES
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
DIMERIZATION
ENDOPLASMIC RETICULUM
HYDROLYSIS
MATURATION
NUCLEOTIDES
Other
OTHER
BIO
PROTEINS