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TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.

Abstract
Mutations that truncate the C-terminal non-catalytic moiety of TTBK2 (tau tubulin kinase 2) cause the inherited, autosomal dominant, SCA11 (spinocerebellar ataxia type 11) movement disorder. In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. We elaborate a peptide substrate (TTBKtide, RRKDLHDDEEDEAMSIYpA) that can be employed to quantify TTBK2 kinase activity. Through modelling and mutagenesis we identify a putative phosphate-priming groove within the TTBK2 kinase domain. We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. We generate an SCA11-mutation-carrying knockin mouse and show that this leads to inhibition of endogenous TTBK2 protein kinase activity. Finally, we find that, in homozygosity, the SCA11 mutation causes embryonic lethality at embryonic day 10. These findings provide the first insights into some of the intrinsic properties of TTBK2 and reveal how SCA11-causing mutations affect protein expression, catalytic activity, localization and development. We hope that these findings will be helpful for future investigation of the regulation and function of TTBK2 and its role in SCA11.
AuthorsMichale Bouskila, Noor Esoof, Laurie Gay, Emily H Fang, Maria Deak, Michael J Begley, Lewis C Cantley, Alan Prescott, Kate G Storey, Dario R Alessi
JournalThe Biochemical journal (Biochem J) Vol. 437 Issue 1 Pg. 157-67 (Jul 01 2011) ISSN: 1470-8728 [Electronic] England
PMID21548880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • tau-tubulin kinase
  • Protein Serine-Threonine Kinases
Topics
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation
  • Phosphorylation
  • Protein Conformation
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Spinocerebellar Ataxias (genetics, metabolism)
  • Spinocerebellar Degenerations
  • Substrate Specificity

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