4U97

Crystal Structure of Asymmetric IRAK4 Dimer


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 

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This is version 1.2 of the entry. See complete history


Literature

IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly.

Ferrao, R.Zhou, H.Shan, Y.Liu, Q.Li, Q.Shaw, D.E.Li, X.Wu, H.

(2014) Mol Cell 55: 891-903

  • DOI: https://doi.org/10.1016/j.molcel.2014.08.006
  • Primary Citation of Related Structures:  
    4U97, 4U9A

  • 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.


  • Organizational Affiliation

    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.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Interleukin-1 receptor-associated kinase 4
A, B
312Homo sapiensMutation(s): 1 
Gene Names: IRAK4
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NWZ3 (Homo sapiens)
Explore Q9NWZ3 
Go to UniProtKB:  Q9NWZ3
PHAROS:  Q9NWZ3
GTEx:  ENSG00000198001 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NWZ3
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.58α = 90
b = 87.58β = 90
c = 421.58γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-09-24
    Type: Initial release
  • Version 1.1: 2014-10-01
    Changes: Database references
  • Version 1.2: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy