4U9A

Sulphur Anomalous Crystal Structure of Asymmetric IRAK4 Dimer

4U9A の概要

• エントリーDOI: 10.2210/pdb4u9a/pdb
• 関連するPDBエントリー: 4U97
• 分子名称: Interleukin-1 receptor-associated kinase 4, STAUROSPORINE, SULFATE ION (3 entities in total)
• 機能のキーワード: kinase, sulphur anomalous, autophosphorylation, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9NWZ3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70862.19

構造登録者

Ferrao, R.,Liu, Q.,Wu, H. (登録日: 2014-08-05, 公開日: 2014-09-24, 最終更新日: 2023-12-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)