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Submitted on December 4, 2006
Revised on April 30, 2007
Accepted on May 15, 2007

Mass spectrometric analysis of the endogenous IL-1RI signalling complex formed after IL-1 binding, identifies IL-1RAcP, MyD88 and IRAK-4 as the stable components

Constantinos Brikos, Robin Wait, Shajna Begum, Luke A. J. O’Neill, and Jeremy Saklatvala

Depatment of Biochemistry, Trinity College, School of Biochemistry and Immunology, Dublin D2

Corresponding Author: brikosc{at}tcd.ie

We investigated the composition of the endogenous ligand-bound type I interleukin-1 receptor (IL-1RI) signalling complex, using immunoprecipitation and tandem mass spectrometry. Three proteins with approximate molecular masses of 60kDa (p60), 36kDa (p36) and 90kDa (p90) became phosphorylated after treatment with IL-1. Phosphorylation in vitro of p60 has been previously reported, but its identity was unknown. We show using tandem mass spectrometry that p60 is identical to IRAK-4. MS also enabled detection of IL-1, IL-1RI, IL-1RAcP and MyD88 in the complex. The p60 protein (IRAK-4) was the earliest component of the complex to be phosphorylated. Phosphorylated IRAK-4 from the receptor complex migrated more slowly in SDS-PAGE than its unphosphorylated form, as did recombinant IRAK-4 autophosphorylated in vitro. Phosphorylation was restricted to serine and threonine residues. IRAK-4, p36, IL-1RAcP and MyD88 bound to the liganded receptor within 15 seconds of activation by IL-1, and remained associated upon prolonged activation, suggesting that the signalling complex is very stable. The p90 phosphoprotein was only transiently associated with the receptor. This behaviour and its size were consistent with its being IRAK-1. Our work reveals that liganding of IL-1RI causes its strong and stable association with IL-1RAcP, MyD88 and the previously unidentified protein p60 (IRAK-4). The only component of the IL-1RI signalling complex that dissociates is IRAK-1. Our study is therefore the first detailed description of the endogenous IL-1RI complex.


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