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Cell Rep. 2017 Sep 19;20(12):2800-2809. doi: 10.1016/j.celrep.2017.08.079.

Structural and Functional Analysis of GRP94 in the Closed State Reveals an Essential Role for the Pre-N Domain and a Potential Client-Binding Site.

Author information

1
Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA; Department of Structural Biology, University at Buffalo, Buffalo, NY, USA.
2
Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA.
3
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
4
Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA; Department of Structural Biology, University at Buffalo, Buffalo, NY, USA. Electronic address: gewirth@hwi.buffalo.edu.

Abstract

Hsp90 chaperones undergo ATP-driven conformational changes during the maturation of client proteins, populating a closed state upon ATP binding in which the N-terminal domains of the homodimer form a second inter-protomer dimer interface. A structure of GRP94, the endoplasmic reticulum hsp90, in a closed conformation has not been described, and the determinants that regulate closure are not well understood. Here, we determined the 2.6-Å structure of AMPPNP-bound GRP94 in the closed dimer conformation. The structure includes the pre-N domain, a region preceding the N-terminal domain that is highly conserved in GRP94, but not in other hsp90s. We show that the GRP94 pre-N domain is essential for client maturation, and we identify the pre-N domain as an important regulator of ATPase rates and dimer closure. The structure also reveals a GRP94:polypeptide interaction that partially mimics a client-bound state. The results provide structural insight into the ATP-dependent client maturation process of GRP94.

KEYWORDS:

GRP94; Hsp90; TRAP1; chaperone

PMID:
28930677
PMCID:
PMC5608278
DOI:
10.1016/j.celrep.2017.08.079
[Indexed for MEDLINE]
Free PMC Article

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