ArticleScientific reports2016
The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.Nature medicine · 2023Trial
- IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation.Nature communications · 2026Article
- Structural basis for selective and potent degradation of IRAK4 by KT-474.Nature communications · 2026Article
- Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review.Experimental hematology & oncology · 2023Review
- IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity.Scientific reports · 2019Article
- Putative link between Polo-like kinases (PLKs) and Toll-like receptor (TLR) signaling in transformed and primary human immune cells.Scientific reports · 2019Article
- Toll-like receptor 4: A promising therapeutic target for pneumonia caused by Gram-negative bacteria.Journal of cellular and molecular medicine · 2019Review
- Toll-like receptor 4 and protease-activated receptor 2 in physiology and pathophysiology of the nervous system: more than just receptor cooperation?Neural regeneration research · 2019Article
- Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling.The Journal of biological chemistry · 2018Article
- Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling.The Journal of biological chemistry · 2018Article
- Interleukin-1 Beta-A Friend or Foe in Malignancies?International journal of molecular sciences · 2018Review
- NF-κB Activation in Lymphoid Malignancies: Genetics, Signaling, and Targeted Therapy.Biomedicines · 2018Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
Activation of Toll-like receptors induces dimerization and the recruitment of the death domain (DD) adaptor protein MyD88 into an oligomeric post receptor complex termed the Myddosome. The Myddosome is a hub for inflammatory and oncogenic signaling and has a hierarchical arrangement with 6-8 MyD88 molecules assembling with exactly 4 of IRAK-4 and 4 of IRAK-2. Here we show that a conserved motif in IRAK-4 (Ser8-X-X-X-Arg12) is autophosphorylated and that the phosphorylated DD is unable to form Myddosomes. Furthermore a mutant DD with the phospho-mimetic residue Asp at this position is impaired in both signalling and Myddosome assembly. IRAK-4 Arg12 is also essential for Myddosome assembly and signalling and we propose that phosphorylated Ser8 induces the N-terminal loop to fold into an α-helix. This conformer is stabilised by an electrostatic interaction between phospho-Ser8 and Arg12 and would destabilise a critical interface between IRAK-4 and MyD88. Interestingly IRAK-2 does not conserve this motif and has an alternative interface in the Myddosome that requires Arg67, a residue conserved in paralogues, IRAK-1 and 3(M).
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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.