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
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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.
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In previously reported closed-state structures the CTD is widened even without a bound H7e, suggesting NTD dimerization alone may cause this.
“in existing closed state structures (Huck et al., 2017; Verba et al., 2016) the CTD adopts this widened conformation in the absence of a bound H7e moiety, indicating this may result from NTD dimerization alone”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Huck et al., 2017
The Results section, “GRP94 containing the pre-N domain forms a closed dimer” (page unavailable), describes a closed-state structure with an N-terminal dimer interface; the client-binding Results section describes a pre-N segment, rather than H7e, in the channel. Our copy does not say that the CTD is widened in this structure or that NTD dimerization alone might cause such widening. (LLM, conf=0.78)
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References 45 · Cited by 73
Research works printed but not linked: 1
- Lee C Park HK Jeong H Lim J Lee AJ Cheon KY Kim CS Thomas AP Bae B Kim ND 2015b Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1 J Am Chem Soc 137 4358 4367 25785725
- Authors
- Huck, J. D., Que, N. L., Hong, F., Li, Z., & Gewirth, D. T.
- Affiliations
- Hauptman-Woodward Medical Research Institute (US)
- Medical University of South Carolina (US)
- Corresponding author
- Gewirth, Daniel T.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 20
- Issue
- 12
- Pages
- 2800-2809
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5608278
- OpenAlex
- W2754267313
- Cited by
- 73
- References
- 45
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 9 · 2020: 2 · 2019: 8 · 2018: 5
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (P01-CA186866, R01-CA095130)
- Avon Foundation for Women (R01-AI070603)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- GRP94, HSP90, closed conformation, ATPase activity, endoplasmic reticulum
- MeSH terms
- Protein Domains, Adenosine Triphosphatases, Animals, Binding Sites, Dogs, Membrane Glycoproteins, Structure-Activity Relationship, Substrate Specificity, HSP90 Heat-Shock Proteins, Protein Multimerization
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