Crystal structure and mechanism of activation of TANK-binding kinase 1

Cell Rep. 2013 Mar 28;3(3):734-46. doi: 10.1016/j.celrep.2013.01.034. Epub 2013 Feb 28.

Abstract

Tank-binding kinase I (TBK1) plays a key role in the innate immune system by integrating signals from pattern-recognition receptors. Here, we report the X-ray crystal structures of inhibitor-bound inactive and active TBK1 determined to 2.6 Å and 4.0 Å resolution, respectively. The structures reveal a compact dimer made up of trimodular subunits containing an N-terminal kinase domain (KD), a ubiquitin-like domain (ULD), and an α-helical scaffold dimerization domain (SDD). Activation rearranges the KD into an active conformation while maintaining the overall dimer conformation. Low-resolution SAXS studies reveal that the missing C-terminal domain (CTD) extends away from the main body of the kinase dimer. Mutants that interfere with TBK1 dimerization show significantly reduced trans-autophosphorylation but retain the ability to bind adaptor proteins through the CTD. Our results provide detailed insights into the architecture of TBK1 and the molecular mechanism of activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism
  • Scattering, Small Angle
  • X-Ray Diffraction

Substances

  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human

Associated data

  • PDB/4IW0
  • PDB/4IWO
  • PDB/4IWP
  • PDB/4IWQ