4U97: Crystal Structure Of Asymmetric Irak4 Dimer

Citation:
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-kappaB activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a KD of 2.5 muM 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.
PDB ID: 4U97Download
MMDB ID: 123485
PDB Deposition Date: 2014/8/5
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 2.65  Å
Source Organism:
Similar Structures:
Biological Unit for 4U97: dimeric; determined by author and by software (PISA)
Molecular Components in 4U97
Label Count Molecule
Proteins (2 molecules)
2
Interleukin-1 Receptor-associated Kinase 4(Gene symbol: IRAK4)
Molecule annotation
Chemicals (5 molecules)
1
2
2
3
* Click molecule labels to explore molecular sequence information.

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