ArticleProceedings of the National Academy of Sciences of the United States of America2013
Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 87 citations in OpenAlex.
- Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism.EMBO reports · 2026Article
- MyD88 self-assembles into supramolecular filaments to amplify NF-κB signaling.Fundamental research · 2026Article
- Emerging host-directed strategies for overcoming drug resistance and immune evasion in Staphylococcus aureus infections.Journal of advanced research · 2026Review
- Structural Mechanism of Receptor-Triggered MyD88 Oligomeric Assembly in Innate Immune Signaling.Nature communications · 2026Article
- TIR-domain-containing protein C as modulator of innate immune checkpoints.Scientific reports · 2025Article
- Combining Network Pharmacology, Molecular Docking, and Integrative Studies to Explore the Mechanism ofFood science & nutrition · 2025Article
- Review
- Characterization of the Structural Requirements for the NADase Activity of Bacterial Toll/IL-1R domains in a Course-based Undergraduate Research Experience.ImmunoHorizons · 2024Article
- Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healingActa pharmaceutica Sinica. B · 2023Article
- Human and Bacterial Toll-Interleukin Receptor Domains Exhibit Distinct Dynamic Features and Functions.Molecules (Basel, Switzerland) · 2022Article
- Immunomodulation therapy offers new molecular strategies to treat UTI.Nature reviews. Urology · 2022Review
- Network Pharmacology- and Molecular Docking-Based Identification of Potential Phytocompounds fromEvidence-based complementary and alternative medicine : eCAM · 2022Article
- Molecular determinants of disease severity in urinary tract infection.Nature reviews. Urology · 2021Review
- TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4.Nature communications · 2021Article
- MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography.Nature communications · 2021Article
- Regulation of Expression of thePathogens (Basel, Switzerland) · 2021Article
- TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88.PLoS pathogens · 2021Article
- Frontline Science: Targeting the TLR7 signalosome assembly.Journal of leukocyte biology · 2020Article
- A survey of TIR domain sequence and structure divergence.Immunogenetics · 2020Article
- Targeting the TLR signalosome with TIR domain-derived cell-permeable decoy peptides: the current state and perspectives.Innate immunity · 2020Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
The Toll/IL-1 receptor (TIR) domains are crucial signaling modules during innate immune responses involving the Toll-like receptors (TLRs) and IL-1 receptor (IL-1R). Myeloid differential factor 88 (MyD88) is a central TIR domain-containing adapter molecule responsible for nearly all TLR-mediated signaling and is targeted by a TIR domain-containing protein C (TcpC) from virulent uropathogenic Escherichia coli, a common human pathogen. The mechanism of such molecular antagonism has remained elusive. We present the crystal structure of the MyD88 TIR domain with distinct loop conformations that underscore the functional specialization of the adapter, receptor, and microbial TIR domains. Our structural analyses shed light on the genetic mutations at these loops as well as the Poc site. We demonstrate that TcpC directly associates with MyD88 and TLR4 through its predicted DD and BB loops to impair the TLR-induced cytokine induction. Furthermore, NMR titration experiments identify the unique CD, DE, and EE loops from MyD88 at the TcpC-interacting surface, suggesting that TcpC specifically engages these MyD88 structural elements for immune suppression. These findings thus provide a molecular basis for the subversion of TLR signaling by the uropathogenic E. coli virulence factor TcpC and furnish a framework for the design of novel therapeutic agents that modulate immune activation.
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