Journal
STRUCTURE
Volume 28, Issue 3, Pages 281-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2020.01.003
Keywords
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Funding
- Wellcome Trust [WT100321/z/12/Z, 108045/Z/15/Z, 206171/Z/17/Z, 202905/Z/16/Z]
- National Institutes of Health [R01 GM60635, P01GM121203]
- Royal Society Research Professorship [RP150066]
- Department of Biochemistry, the School of Biological Sciences, and the University of Cambridge
- Department of Chemistry, the School of Clinical Medicine, and the University of Cambridge
- Wellcome Trust [202905/Z/16/Z, 206171/Z/17/Z] Funding Source: Wellcome Trust
- BBSRC [BB/H003916/1] Funding Source: UKRI
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Toll-like receptors (TLRs) are pivotal in triggering the innate immune response to pathogen infection. Ligand binding induces receptor dimerization which facilitates the recruitment of other post-receptor signal transducers into a complex signalosome, the Myddosome. Central to this process is Myeloid differentiation primary response 88 (MyD88), which is required by almost all TLRs, and signaling is thought to proceed via the stepwise, sequential assembly of individual components. Here, we show that the death domains of human MyD88 spontaneously and reversibly associate to form helical filaments in vitro. A 3.1-angstrom cryoelectron microscopy structure reveals that the architecture of the filament is identical to that of the 6:4 MyD88-IRAK4-IRAK2 heterooligomeric Myddosome. Additionally, the death domain of IRAK4 interacts with the filaments to reconstitute the non-stoichiometric 6:4 MyD88-IRAK4 complex. Together, these data suggest that intracellularly, the MyD88 scaffold may be preformed and poised for recruitment of IRAKs on receptor activation and TIR engagement.
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