ArticleThe Journal of biological chemistry2012
The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 94 citations in OpenAlex.
- Heat shock protein Gp96 (Grp94) in malaria: functional insights at the host-parasite interface and therapeutic perspectives.Frontiers in cell and developmental biology · 2026Review
- Heat shock proteins at the crossroads of endosomal trafficking pathways.Cell biology and toxicology · 2025Review
- Hsp90Pharmaceuticals (Basel, Switzerland) · 2025Review
- Conformationally Restricted Grp94-Selective Inhibitors.ACS omega · 2025Article
- GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes.Cell death & disease · 2024Article
- Structural transitions modulate the chaperone activities of Grp94.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- The biology and inhibition of glucose-regulated protein 94/gp96.Medicinal research reviews · 2022Review
- Active nNOS Is Required for Grp94-Induced Antioxidant Cytoprotection: A Lesson from Myogenic to Cancer Cells.International journal of molecular sciences · 2022Article
- Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases.iScience · 2021Article
- Protective Role of Genetic Variants in HSP90 Genes-Complex in COPD Secondary to Biomass-Burning Smoke Exposure and Non-Severe COPD Forms in Tobacco Smoking Subjects.Current issues in molecular biology · 2021Article
- Broadly Protective CD8Journal of virology · 2021Article
- Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy.Cells · 2021Review
- Biological Evaluation of 5'-(ACS medicinal chemistry letters · 2021Article
- The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function.Frontiers in physiology · 2021Review
- Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target.Frontiers in oncology · 2021Review
- ENPL-1, theDevelopment (Cambridge, England) · 2020Article
- Harnessing the Proteostasis Network in Alcohol-associated Liver Disease.Current pathobiology reports · 2020Article
- Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production.Cells · 2020Review
- Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage.Scientific reports · 2020Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
The structural basis for molecular chaperones to discern misfolded proteins has long been an enigma. As the endoplasmic reticulum paralogue of the cytosolic HSP90, gp96 (GRP94, HSP90b1) is an essential molecular chaperone for Toll-like receptors (TLRs) and integrins. However, little is known about its client-binding domain (CBD). Herein, we provide genetic and biochemical evidence to definitively demonstrate that a C-terminal loop structure, formed by residues 652-678, is the critical region of CBD for both TLRs and integrins. Deletion of this region affects neither the intrinsic ATPase activity nor the overall conformation of gp96. However, without it, the chaperoning function of gp96 collapses. We also find a critical Met pair (Met(658)-Met(662)) for the folding of integrins but not TLRs. Moreover, we find that the TLR binding to gp96 is also dependent on the C-terminal dimerization domain but not the N-terminal ATP-binding pocket of gp96. Our study has unveiled surprisingly the exquisite specificity of gp96 in substrate binding and suggests a manipulation of its CBD as an alternative strategy for targeted therapy of a variety of diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.