Accès ouvert

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

Article scientifique 2016 Anglais

Résumé

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).

Citer ce document

Dossang, A., Motshwene, P., Yang, Y., Symmons, M., Bryant, C., Borman, S., George, J., Weber, A., Gay, N. (2016). The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold. https://doi.org/10.1038/srep37267

Accès au document

Voir sur le dépôt source

Ce document est hébergé sur son dépôt institutionnel d'origine.

Auteur(s)

Anthony Dossang Precious G. Motshwene Yang Yang Martyn F. Symmons Clare Bryant Satty Borman Julie George Alexander N.R. Weber Nicholas J. Gay

Statistiques

Consultations : 3

Téléchargements : 0