ArticleThe Journal of biological chemistry2011
The ectodomain of the Toll-like receptor 4 prevents constitutive receptor activation.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- Genetically inducible coordinators of cytokine signaling pathways for interrogating T cell motility.bioRxiv : the preprint server for biology · 2026Article
- Toll-like receptor 4 signaling activation domains promote CAR T cell function against solid tumors.Molecular therapy. Oncology · 2024Article
- Article
- Full-Atom Model of the Agonist LPS-Bound Toll-like Receptor 4 Dimer in a Membrane Environment.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Light-Inducible Spatio-Temporal Control of TLR4 and NF-κB-Gluc Reporter in Human Pancreatic Cell Line.International journal of molecular sciences · 2021Article
- TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling.Cellular and molecular life sciences : CMLS · 2021Review
- Toll-Like Receptors: General Molecular and Structural Biology.Journal of immunology research · 2021Review
- Exploring electrostatic patterns of human, murine, equine and canine TLR4/MD-2 receptors.Innate immunity · 2020Article
- Saturated Fatty Acids in Obesity-Associated Inflammation.Journal of inflammation research · 2020Review
- Toll-like receptors and their role in persistent pain.Pharmacology & therapeutics · 2018Review
- Spatial structure of TLR4 transmembrane domain in bicelles provides the insight into the receptor activation mechanism.Scientific reports · 2017Article
- SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Drugging Membrane Protein Interactions.Annual review of biomedical engineering · 2016Review
- Contributions of unique intracellular domains to switchlike biosensing by Toll-like receptor 4.The Journal of biological chemistry · 2015Article
- Article
- Modular extracellular sensor architecture for engineering mammalian cell-based devices.ACS synthetic biology · 2014Article
- Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization.Blood · 2014Article
- Assembly and localization of Toll-like receptor signalling complexes.Nature reviews. Immunology · 2014Review
- The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane.Science signaling · 2014Article
- Cytokine Spatzle binds to the Drosophila immunoreceptor Toll with a neurotrophin-like specificity and couples receptor activation.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toll-like receptor 4 (TLR4) is involved in activation of the innate immune response in a large number of different diseases. Despite numerous studies, the role of separate domains of TLR4 in the regulation of receptor activation is poorly understood. Replacement of the TLR4 ectodomain with LPS-binding proteins MD-2 or CD14 resulted in a robust ligand-independent constitutive activation comparable with the maximal stimulation of the receptor with LPS. The same effect was achieved by the replacement of the ectodomain with a monomeric fluorescent protein or a 24-kDa gyrase B fragment. This demonstrates an intrinsic dimerization propensity of the transmembrane and cytoplasmic domains of TLR4 and reveals a previously unknown function of the ectodomain in inhibiting spontaneous receptor dimerization. Constitutive activation was abolished by the replacement of the ectodomain by a bulkier protein ovalbumin. N-terminal deletion variants of TLR4 revealed that the smallest segment of the ectodomain that already prevents constitutive activity comprises only 90 residues (542 to 631) of the total 608 residues. We conclude that TLR4 represents a receptor with a low threshold of activation that can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. The TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization.
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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.