Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling

Abstract

MyD88, IRAK4 and IRAK2 are critical signaling 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 signaling 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 signaling 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 signaling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.

Prion-like behavior of MAVS in RIG-I signaling

“…It seems plausible that the MyD88 and MAVS adapter complexes, both of which signal to TRAF6 and TRAF3, bear some structural similarity, at least at the interface with these TRAFs, that permit them to interact with and/or activate the TRAFs. Recently, the crystal structure of the signaling complex formed by the death domains (DDs) of MyD88, IRAK4, and IRAK2, termed the Myddosome, was reported [14]. Like the isolated CARD domain of MAVS [15], the DD of MyD88, IRAK4, and IRAK2 folds into a six-helix bundle; six MyD88, four IRAK4, and four IRAK2 DDs are arranged in a left-handed helix in the Myddosome, triggering downstream signaling.…”

Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

“…Such inhibitions may be caused by dominant negative effect of truncated CgMyD88. Further, we first looked into the structure of Myddosome complex, which is composed of 6 MyD88, 4 IRAK4 and 4 IRAK2 death domain (DD) [29]. CgMyD88 variants can participate in the formation of Myddosome complex through binding with other TIR domaincontaining proteins, such as TLR or Myd88, but can not recruit downstream signaling protein IRAK4 due to its lack of DD domain.…”

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

“…Interactions between MyD88 and IRAK kinases are mediated in a DD-dependent manner. 8,9 To test whether Unc5CL can also interact with IRAKs, co-immunoprecipitation experiments have been performed (Figure 5e). Wild-type or kinase-dead IRAK4 (IRAK4 kd) were co-expressed with Unc5CL 432G, Unc5CLDDD or Unc5CL 432R.…”

“…MyD88 then nucleates the assembly of a ternary protein complex via DD-dependent recruitment and activation of the kinases IRAK1, IRAK2 and IRAK4. 8,9 Together with the E3-ubiquitin ligase TRAF6 these factors mediate further propagation of the signal. 10 The importance of the TLR/IL-1R signaling axis in health and disease is highlighted by the association with a multitude of human malignancies.…”