4U9A

Sulphur Anomalous Crystal Structure of Asymmetric IRAK4 Dimer

Summary for 4U9A

• Entry DOI: 10.2210/pdb4u9a/pdb
• Related: 4U97
• Descriptor: Interleukin-1 receptor-associated kinase 4, STAUROSPORINE, SULFATE ION (3 entities in total)
• Functional Keywords: kinase, sulphur anomalous, autophosphorylation, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9NWZ3
• Total number of polymer chains: 2
• Total formula weight: 70862.19

Authors

Ferrao, R.,Liu, Q.,Wu, H. (deposition date: 2014-08-05, release date: 2014-09-24, Last modification date: 2023-12-27)

Primary citation

Ferrao, R.,Zhou, H.,Shan, Y.,Liu, Q.,Li, Q.,Shaw, D.E.,Li, X.,Wu, H.
IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly.
Mol.Cell, 55:891-903, 2014

PubMed 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.

PubMed: 25201411
DOI: 10.1016/j.molcel.2014.08.006

Experimental method

X-RAY DIFFRACTION (2.8 Å)