title: Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation.
abstract: Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.
authors.affiliation: Departments of Structural Biology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Helgason
authors.forename: Qui T
authors.initials: QT
authors.lastname: Phung
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Quan
authors.forename: Rekha S
authors.initials: RS
authors.lastname: Iyer
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Lee
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: Erin C
authors.initials: EC
authors.lastname: Dueber
mesh_terms: D002384:Catalysis; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human