Tau-tubulin kinase

Function

Tau-tubulin kinase (TTBK) phosphorylates microtubule-associated protein tau and tubulin^[1]. TTBK contains 2 isomers: TTBK1 and TTBK2 which are expressed in different tissues. TTBK1 and TTBK2 are homologous in their catalytic domains with identical catalytic residues, but different in their non-catalytic domains. TTBK2 serves a critical function in cilia genesis^[2].

Disease

Mutations in TTBK1 and in particular the R142Q mutation is involved in taupathogenesis like in Alzheimer Disease^[3].

Relevance

TTBK1 inhibitors are promising candidates for Alzheimer Disease therapy^[4]. TTBK1 phosphorylates TDP-43 and thus its inhibitors can be promising therapeutic targets for treatment of ALS^[5].

Structural highlights

^[6].

Tau-tubulin kinase 3D structures

Tau-tubulin kinase 3D structures

References

1. ↑ Ikezu S, Ikezu T. Tau-tubulin kinase. Front Mol Neurosci. 2014 Apr 28;7:33. PMID:24808823 doi:10.3389/fnmol.2014.00033
2. ↑ Liao JC, Yang TT, Weng RR, Kuo CT, Chang CW. TTBK2: a tau protein kinase beyond tau phosphorylation. Biomed Res Int. 2015;2015:575170. PMID:25950000 doi:10.1155/2015/575170
3. ↑ Ahamad S, Hema K, Kumar V, Gupta D. The structural, functional, and dynamic effect of Tau tubulin kinase1 upon a mutation: A neuro-degenerative hotspot. J Cell Biochem. 2021 Nov;122(11):1653-1664. PMID:34297427 doi:10.1002/jcb.30112
4. ↑ Martinez-Gonzalez L, Cuevas EP, Tosat-Bitrián C, Nozal V, Gil C, Palomo V, Martín-Requero Á, Martinez A. TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer's disease patients. Front Mol Neurosci. 2023 Aug 9;16:1243277. PMID:37621404 doi:10.3389/fnmol.2023.1243277
5. ↑ Nozal V, Martinez-Gonzalez L, Gomez-Almeria M, Gonzalo-Consuegra C, Santana P, Chaikuad A, Perez-Cuevas E, Knapp S, Lietha D, Ramirez D, Petralla S, Monti B, Gil C, Martin-Requero A, Palomo V, de Lago E, Martinez A. TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy. J Med Chem. 2022 Jan 27;65(2):1585-1607. doi: 10.1021/acs.jmedchem.1c01942. Epub , 2022 Jan 3. PMID:34978799 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01942
6. ↑ Xue Y, Wan PT, Hillertz P, Schweikart F, Zhao Y, Wissler L, Dekker N. X-ray Structural Analysis of Tau-Tubulin Kinase 1 and Its Interactions with Small Molecular Inhibitors. ChemMedChem. 2013 Sep 13. doi: 10.1002/cmdc.201300274. PMID:24039150 doi:10.1002/cmdc.201300274