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

Huck, John D.; Que, Nanette L.S.; Hong, Feng; Li, Zihai; Gewirth, D.T.

doi:10.1016/j.celrep.2017.08.079

Cited by 56 publications

(99 citation statements)

References 44 publications

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“…1A) (1,9,38). This extension is absent in bacterial Hsp90, Grp94, and TRAP1, consistent with the fact that homologs of the Hsp90 TPR co-chaperones are not found in bacteria and eukaryotic organelles (1,9,29,30).…”

Section: Domain Arrangement Of Hsp90 Protomerssupporting

confidence: 64%

“…1D) (41) and GRP94 with AMP-PNP bound ( Fig. 1E) (30) are similar to that of the Hsp90 Ec -AMP-PNP dimer (32), suggesting that the conformations may be conserved. Similarly, the apo and ADP-bound conformations are also likely to be conserved (40).…”

Section: Dimeric Structure Of Hsp90mentioning

confidence: 58%

“…1A). One feature is a long, flexible, charged linker that connects the NTD and the MD in cytosolic eukaryotic Hsp90 as well as endoplasmic reticulum Hsp90, Grp94 (15,29,30), which is absent in bacterial Hsp90 and mitochondrial Hsp90, TRAP1 (15,31,32). This charged linker has been proposed to function as a modulator of Hsp90 conformational changes and co-chaperone binding (33)(34)(35)(36)(37).…”

Section: Domain Arrangement Of Hsp90 Protomersmentioning

confidence: 99%

“…Although the Hsp90 dimer is symmetric in many structures ( Fig. 1, B-E) (29,30,32,41), a recent structure of mitochondrial Hsp90, TRAP1, in the AMP-PNP-bound state shows an asymmetric conformation at the interface between the MD and CTD ( Fig. 1F) (31).…”

Section: Dimeric Structure Of Hsp90mentioning

confidence: 99%

“…D, dimer structure of Saccharomyces cerevisiae Hsp82 in the AMP-PNP-bound conformation (PDB code 2CG9) (41). E, dimer structure of Canis lupus familiaris endoplasmic reticulum Hsp90, GRP94, in the AMP-PNP-bound conformation (PDB code 5ULS) (30). F, dimer structure of Danio rerio (zebrafish) mitochondrial Hsp90, TRAP1, in the AMP-PNP-bound conformation (PDB code 4IPE) (31).…”

Section: Domain Arrangement Of Hsp70mentioning

confidence: 99%

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Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling

Genest¹,

Wickner²,

Doyle³

2019

Journal of Biological Chemistry

270

194

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Heat shock proteins 90 (Hsp90) and 70 (Hsp70) are two families of highly conserved ATP-dependent molecular chaperones that fold and remodel proteins. Both are important components of the cellular machinery involved in protein homeostasis and participate in nearly every cellular process. Although Hsp90 and Hsp70 each carry out some chaperone activities independently, they collaborate in other cellular remodeling reactions. In eukaryotes, both Hsp90 and Hsp70 function with numerous Hsp90 and Hsp70 co-chaperones. In contrast, bacterial Hsp90 and Hsp70 are less complex; Hsp90 acts independently of cochaperones, and Hsp70 uses two co-chaperones. In this review, we focus on recent progress toward understanding the basic mechanisms of Hsp90-mediated protein remodeling and the collaboration between Hsp90 and Hsp70, with an emphasis on bacterial chaperones. We describe the structure and conformational dynamics of these chaperones and their interactions with each other and with client proteins. The physiological roles of Hsp90 in Escherichia coli and other bacteria are also discussed. We anticipate that the information gained from exploring the mechanism of the bacterial chaperone system will provide the groundwork for understanding the more complex eukaryotic Hsp90 system and its modulation by Hsp90 co-chaperones.

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Section: Domain Arrangement Of Hsp90 Protomerssupporting

confidence: 64%

Section: Dimeric Structure Of Hsp90mentioning

confidence: 58%

Section: Domain Arrangement Of Hsp90 Protomersmentioning

confidence: 99%

Section: Dimeric Structure Of Hsp90mentioning

confidence: 99%

Section: Domain Arrangement Of Hsp70mentioning

confidence: 99%

See 3 more Smart Citations

Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling

Genest¹,

Wickner²,

Doyle³

2019

Journal of Biological Chemistry

270

194

View full text Add to dashboard Cite

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The biology and inhibition of glucose‐regulated protein 94/gp96

Pugh

Alnaed

Brackett

et al. 2022

Medicinal Research Reviews

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The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic reticulum (ER) stress and disease. Grp94 belongs to the Hsp90 family of molecular chaperones and is a master regulator of ER homeostasis due to its ability to fold and stabilize proteins/receptors, and to chaperone misfolded proteins for degradation. Multiple studies have demonstrated that Grp94 knockdown or inhibition leads to the degradation of client protein substrates, which leads to disruption of disease-dependent signaling pathways. As a result, small molecule inhibitors of Grp94 have become a promising therapeutic approach to target a variety of disease states. Specifically, Grp94 has proven to be a promising target for cancer, glaucoma, immune-mediated inflammation, and viral infection. Moreover, Grp94-peptide complexes have been utilized effectively as adjuvants for vaccines against a variety of disease states. This work highlights the significance of Grp94 biology and the development of therapeutics that target this molecular chaperone in multiple disease states.

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Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94‐Selective Ligand Binding

Que,

Seidler,

et al. 2024

Proteins

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Grp94 is the endoplasmic reticulum paralog of the hsp90 family of chaperones, which have been targeted for therapeutic intervention via their highly conserved ATP binding sites. The design of paralog‐selective inhibitors relies on understanding the protein structural elements that drive higher affinity in selective inhibitors. Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94‐selective inhibitor PU‐H36, and of Grp94 with the non‐selective inhibitor PU‐H71. In Grp94, PU‐H36 derives its higher affinity by utilizing Site 2, a Grp94‐specific side pocket adjoining the ATP binding cavity, but in Hsp90 PU‐H36 occupies Site 1, a side pocket that is accessible in all paralogs with which it makes lower affinity interactions. The structure of Grp94 in complex with PU‐H71 shows only Site 1 binding. While changes in the conformation of helices 4 and 5 in the N‐terminal domain occur when ligands bind to Site 1 of both Hsp90 and Grp94, large conformational shifts that also involve helix 1 are associated with the engagement of the Site 2 pocket in Grp94 only. Site 2 in Hsp90 is blocked and its helix 1 conformation is insensitive to ligand binding. To understand the role of helix 1 in ligand selectivity, we tested the binding of PU‐H36 and other Grp94‐selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 is the major determinant of selectivity for Site 2 targeted ligands and also influences the rate of ATPase activity in Hsp90 paralogs.

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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

Cited by 56 publications

References 44 publications

Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling

Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling

The biology and inhibition of glucose‐regulated protein 94/gp96

Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94‐Selective Ligand Binding

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