ArticleProceedings of the National Academy of Sciences of the United States of America2022
The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Immunoglobulin binding protein (BiP) forms two types of dimers.Protein science : a publication of the Protein Society · 2026Article
- The integrated stress response in pancreatic β-cell failure in diabetes: from molecular mechanisms to precision therapeutics.Frontiers in endocrinology · 2026Review
- Heat shock protein Gp96 (Grp94) in malaria: functional insights at the host-parasite interface and therapeutic perspectives.Frontiers in cell and developmental biology · 2026Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Two-Color Timestamping of Gene Expression with a Chemigenetic Reporter System.Chembiochem : a European journal of chemical biology · 2025Article
- Conformational plasticity of a BiP-GRP94 chaperone complex.Nature structural & molecular biology · 2025Article
- The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery.Trends in pharmacological sciences · 2025Review
- Mechanism of client loading from BiP to Grp94 and its disruption by select inhibitors.Nature communications · 2025Article
- Hsp90: Bringing it all together.Cell stress & chaperones · 2025Review
- The Essential Functions of Molecular Chaperones and Folding Enzymes in Maintaining Endoplasmic Reticulum Homeostasis.Journal of molecular biology · 2024Review
- Long non-coding RNA-mediated modulation of endoplasmic reticulum stress under pathological conditions.Journal of cellular and molecular medicine · 2024Review
- The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.Journal of biomedical science · 2024Review
- Hsp90, a team player in protein quality control and the stress response in bacteria.Microbiology and molecular biology reviews : MMBR · 2024Review
- Tracing genetic diversity captures the molecular basis of misfolding disease.Nature communications · 2024Article
- Structural transitions modulate the chaperone activities of Grp94.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Visualization of conformational transition of GRP94 in solution.Life science alliance · 2024Article
- Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics.The journal of physical chemistry. B · 2023Article
- Protective Effect and Mechanism of Xbp1s Regulating HBP/O-GlcNAcylation through GFAT1 on Brain Injury after SAH.Biomedicines · 2023Article
- A proinsulin-dependent interaction between ENPL-1 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.Development (Cambridge, England) · 2023Article
- Growth Hormone-Releasing Hormone in Endothelial Inflammation.Endocrinology · 2022Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.
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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.