ArticleThe Journal of biological chemistry2018
The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed.
- Thbs1Journal of advanced research · 2026Article
- Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma.EMBO molecular medicine · 2026Article
- The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes.Pharmacological reports : PR · 2026Article
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- The integrated stress response in pancreatic β-cell failure in diabetes: from molecular mechanisms to precision therapeutics.Frontiers in endocrinology · 2026Review
- Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.Frontiers in cell and developmental biology · 2026Review
- Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment.Cell death discovery · 2025Review
- Bacterial infection elicits theOpen biology · 2025Article
- Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.Cell metabolism · 2025Article
- Developments in the connection between epithelial‑mesenchymal transition and endoplasmic reticulum stress (Review).International journal of molecular medicine · 2025Review
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- The integrated stress response in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- Cryo-EM structure of histidyl-tRNA synthetase-like domain reveals activating crossed helices at the core of GCN2.PNAS nexus · 2024Article
- Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke.iScience · 2024Article
- IRE1α recognizes a structural motif in cholera toxin to activate an unfolded protein response.The Journal of cell biology · 2024Article
- Article
- Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response.Redox biology · 2024Article
- The dual effect of endoplasmic reticulum stress in digestive system tumors and intervention of Chinese botanical drug extracts: a review.Frontiers in pharmacology · 2024Review
23 more citing papers are in PubMed but not listed here.
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4 authors.
Funding
Abstract
PRKR-like endoplasmic reticulum kinase (PERK) is one of the major sensor proteins that detect protein folding imbalances during endoplasmic reticulum (ER) stress. However, it remains unclear how ER stress activates PERK to initiate a downstream unfolded protein response (UPR). Here, we found that PERK's luminal domain can recognize and selectively interact with misfolded proteins but not with native proteins. Screening a phage-display library, we identified a peptide substrate, P16, of the PERK luminal domain and confirmed that P16 efficiently competes with misfolded proteins for binding this domain. To unravel the mechanism by which the PERK luminal domain interacts with misfolded proteins, we determined the crystal structure of the bovine PERK luminal domain complexed with P16 to 2.8-Å resolution. The structure revealed that PERK's luminal domain binds the peptide through a conserved hydrophobic groove. Substitutions within hydrophobic regions of the PERK luminal domain abolished the binding between PERK and misfolded proteins. We also noted that peptide binding results in major conformational changes in the PERK luminal domain that may favor PERK oligomerization. The structure of the PERK luminal domain-P16 complex suggested stacking of the luminal domain that leads to PERK oligomerization and activation via autophosphorylation after ligand binding. Collectively, our structural and biochemical results strongly support a ligand-driven model in which the PERK luminal domain interacts directly with misfolded proteins to induce PERK oligomerization and activation, resulting in ER stress signaling and the UPR.
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