| Structural highlights
Function
TLK2_HUMAN Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation. Phosphorylates the chromatin assembly factors ASF1A AND ASF1B. Phosphorylation of ASF1A prevents its proteasome-mediated degradation, thereby enhancing chromatin assembly. Negative regulator of amino acid starvation-induced autophagy.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.
Molecular basis of Tousled-Like Kinase 2 activation.,Mortuza GB, Hermida D, Pedersen AK, Segura-Bayona S, Lopez-Mendez B, Redondo P, Ruther P, Pozdnyakova I, Garrote AM, Munoz IG, Villamor-Paya M, Jauset C, Olsen JV, Stracker TH, Montoya G Nat Commun. 2018 Jun 28;9(1):2535. doi: 10.1038/s41467-018-04941-y. PMID:29955062[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sillje HH, Takahashi K, Tanaka K, Van Houwe G, Nigg EA. Mammalian homologues of the plant Tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication. EMBO J. 1999 Oct 15;18(20):5691-702. PMID:10523312 doi:https://dx.doi.org/10.1093/emboj/18.20.5691
- ↑ Sillje HH, Nigg EA. Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Curr Biol. 2001 Jul 10;11(13):1068-73. PMID:11470414
- ↑ Groth A, Lukas J, Nigg EA, Sillje HH, Wernstedt C, Bartek J, Hansen K. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J. 2003 Apr 1;22(7):1676-87. PMID:12660173 doi:10.1093/emboj/cdg151
- ↑ Krause DR, Jonnalagadda JC, Gatei MH, Sillje HH, Zhou BB, Nigg EA, Khanna K. Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene. 2003 Sep 4;22(38):5927-37. doi: 10.1038/sj.onc.1206691. PMID:12955071 doi:https://dx.doi.org/10.1038/sj.onc.1206691
- ↑ Pilyugin M, Demmers J, Verrijzer CP, Karch F, Moshkin YM. Phosphorylation-mediated control of histone chaperone ASF1 levels by Tousled-like kinases. PLoS One. 2009 Dec 16;4(12):e8328. doi: 10.1371/journal.pone.0008328. PMID:20016786 doi:https://dx.doi.org/10.1371/journal.pone.0008328
- ↑ McKnight NC, Jefferies HB, Alemu EA, Saunders RE, Howell M, Johansen T, Tooze SA. Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. EMBO J. 2012 Apr 18;31(8):1931-46. doi: 10.1038/emboj.2012.36. Epub 2012 Feb 21. PMID:22354037 doi:10.1038/emboj.2012.36
- ↑ Yamakawa A, Kameoka Y, Hashimoto K, Yoshitake Y, Nishikawa K, Tanihara K, Date T. cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal. Gene. 1997 Nov 20;202(1-2):193-201. PMID:9427565
- ↑ Mortuza GB, Hermida D, Pedersen AK, Segura-Bayona S, Lopez-Mendez B, Redondo P, Ruther P, Pozdnyakova I, Garrote AM, Munoz IG, Villamor-Paya M, Jauset C, Olsen JV, Stracker TH, Montoya G. Molecular basis of Tousled-Like Kinase 2 activation. Nat Commun. 2018 Jun 28;9(1):2535. doi: 10.1038/s41467-018-04941-y. PMID:29955062 doi:https://dx.doi.org/10.1038/s41467-018-04941-y
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