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Mol Cell. 2014 Sep 18;55(6):891-903. doi: 10.1016/j.molcel.2014.08.006. Epub 2014 Sep 4.

IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
2
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
3
D.E. Shaw Research, New York, NY 10036, USA.
4
New York Structural Biology Center, National Synchrotron Light Source X4, Brookhaven National Laboratory, Upton, NY 11961, USA.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
6
D.E. Shaw Research, New York, NY 10036, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
7
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: hao.wu@childrens.harvard.edu.

Abstract

Trans-autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane-proximal adaptor MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-κB activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a KD of 2.5 μM and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-KD concentrations. The crystal structure of the unphosphorylated IRAK4(KD) dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show that dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation.

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PMID:
25201411
PMCID:
PMC4169746
DOI:
10.1016/j.molcel.2014.08.006
[Indexed for MEDLINE]
Free PMC Article

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