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The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold

Published version
Peer-reviewed

Type

Article

Change log

Authors

Dossang, ACG 
Motshwene, PG 
Yang, Y 
Symmons, MF 
Bryant, CE 

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).

Description

Keywords

Amino Acid Motifs, Humans, Interleukin-1 Receptor-Associated Kinases, Multiprotein Complexes, Myeloid Differentiation Factor 88, Protein Structure, Quaternary, Signal Transduction, Static Electricity

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

6

Publisher

Nature Publishing Group
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/H003916/1)
Medical Research Council (G1000133)
This work was supported by program grants from the Wellcome Trust (WT081744/Z/06/Z) and the UK Medical Research Council (G1000133) to N.J.G. and C.E.B. and a Wellcome Investigator award to N.J.G. (WT100321/z/12/Z). AD was the recipient of a studentship award from GlaxoSmithKline. JG was supported by the German Cancer Research Center (DKFZ). ANRW was supported by the Else-Kröner-Fresenius-Stiftung, the German Research Foundation (Grant SFB685 “Immunotherapy”) and the University of Tübingen. PGM was supported by a Thuthuka Grant from the S. African NRF (TTK14060668443).