title: Crystal structure and mechanism of activation of TANK-binding kinase 1.
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.
authors: EMBL Grenoble, 6 Rue Jules Horowitz, Grenoble 38042, France.
authors: Amede
authors: A
authors: Larabi
authors: Juliette M
authors: JM
authors: Devos
authors: Sze-Ling
authors: SL
authors: Ng
authors: Max H
authors: MH
authors: Nanao
authors: Adam
authors: A
authors: Round
authors: Tom
authors: T
authors: Maniatis
authors: Daniel
authors: D
authors: Panne
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human