Helical assembly in the MyD88:IRAK4:IRAK2 complex in TLR/IL-1R signaling

By Su-Chang Lin, Y. Lo, Hao Wu. Nature, 2010

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MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88–IRAK4–IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88–IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88–IRAK4–IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/a0fd56f2b8c27f0212922d573d41378688c32740

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Citations in the corpus

Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “Upon TLR4 activation, MyD88 oligomerizes to form a large signaling platform called a myddosome, which incorporates 6–8 MyD88 molecules, TIRAP, and members of the IRAK family (81, 83, 84).”
The Structural Biology of Toll-Like Receptors (2011, background): “[PubMed: 18172197] Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.”
Toll-Like Receptor Signaling Pathways (2014, background): “MyD88-DEPENDENT PATHWAY After TLR engagement, MyD88 forms a complex with IRAK kinase family members, referred to as the Myddosome (Figure 1) (42).”
Unified Polymerization Mechanism for the Assembly of ASC-dependent Inflammasomes (2014, background): “In the previously observed DD/DD interactions, type I is mediated by residues at a1 and a4 (type Ia) and residues at a2 and a3 (type Ib) (Ferrao andWu, 2012; Lin et al., 2010; Park et al., 2007).”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “Similarly, yet distinctly, the oligomeric scaffold of the DD superfamily mediates caspase activation and apoptosis (Wang et al., 2010), as well as MyD88dependent Toll-like receptor signaling (Lin et al., 2010).”
Pathogen Recognition by the Innate Immune System (2011, background): “Recently, the crystal structure of the MyD88-IRAK4-IRAK2 complex was reported and shows a left-handed helical oligomeric signaling complex, which consists of six, four, and four molecules of MyD88, IRAK4, and the IRAK2 death domain, respectively [30].”
Signaling in innate immunity and inflammation. (2012, background): “The MyD88–IRAK4–IRAK1–TRAF6 signaling complex required for pro-inflammatory cytokine production by TLR7 and TLR9 also stimulates synthesis of interferon a (IFNa) and IFNb in plasmacytoid dendritic cells (pDCs).”
The Drosophila Toll Signaling Pathway (2011, background): “In mammals, six MyD88, four IRAK4, and four IRAK2 DDs form a helical oligomer complex called Myddosome for downstream signaling (98).”
Molecular Basis of NF-κB Signaling (2013, background): “Surface shape and charge complementarity between the adjacent layers and the fact that the IRAK4DDis monomeric whereas the DD of MyD88 is prone to oligomerization in solution suggests a sequential assembly order of the entire complex (66).”