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  • Aurora kinase B AURKB and haploid cell specific protein kina

    2022-01-14

    Aurora kinase B (AURKB) and haploid cell-specific protein kinase (Haspin) are two well-known participants in N-terminal histone H3 phosphorylations during mitosis. A related role played by these kinases relates to the fact that AURKB is activated by Haspin promoted phosphorylation at T3. Irrespective of the presence of several other sites, AURKB promotes phosphorylation at S10 and S28 solely. This finding indicates that amino fda approved vegf inhibitor sequences before and after the phosphorylation site must govern phosphorylation specificity. A conserved RKSP amino acid sequence at the phosphorylation site exists not only in the N-terminal histone H3 but also in the RNA methyltransferase NSUN2 of vertebrates. T3 residue of N-terminal histone H3 is the only known phosphorylation site for Haspin as its substrate. Phosphorylation of H3 N-terminal is directly recognized by Survvin, which is a component of chromosomal passenger complex during mitosis. Even though phosphorylation is one of the most important PTMs in histone H3, previous observations suggest that this process is not the sole type of modification that leads to physiological changes. For example, there are novel histone H3 methyltransferases that are required for heterochromation formation. If multiple PTMs are responsible for important biological marking, additional specificity must be present to serve as embedded combinatorial markers for phosphorylation. A brief comment was made describing the control of Haspin phosphorylation rates by neighbouring methylations, However, a comprehensive study of the variations of AURKB and Haspin activities by epigenetic PTMs of neighboring amino acids has not been conducted yet despite the fact that cooperative interactions exist for this phosphorylation process during histone mediated cellular events.16, 17 In the current investigation, we have attempted to elucidate the specificities of AURKB and Haspin by using peptides that contain all possible PTMs in the histone H3 N-terminal peptides. Kinase activities of AURKB and Haspin are reduced in a manner that depends on the position and type of the PTM. In cases where the kinase activity is reduced substantially by other modifications, dimethylation at R2 and R8 leads to totally abolishment of phosphorylation at S10 by AURKB and dimethylation at R2 and trimethylation at K4 causes the same effect on phosphorylation at T3 by Haspin.
    Results and discussion
    Conclusion In summary, a variety of epigenetically modified short peptides that mimic the H3 histone N-terminus were prepared and their activities as substrates for AURKB and Haspin promoted phosphorylation were determined in this effort. The data obtained in this effort demonstrate that the activity of AURKB is sensitive to short- and long-range modifications, while that of Haspin is sensitive to only short-range modifications. The most important findings in this work are that (1) dimethylation at R2 and R8 leads to peptides that have non-existent activities for AUKRB and Haspin, (2) peptides with methylation modifications at K4 and K9 have reduced rates of phosphorylation promoted by AURKB and Haspin, while dimethylation as seen in K4Me3 has a significant effect in diminishing the activity of Haspin, (3) phosphorylation at T3 or S10 significantly reduces the rates of phosphorylation at the other site suggesting that a dual phosphorylation at T3 and S10 might not be one of as ‘histone code’, and (4) peptides containing acetylation at K4 and K14 have greatly reduced kinase activities for both AURKB and Haspin. As shown in Figure 4, AURKB is affected by a wide range of modifications close to or distant from R2 to K14, while Haspin is only significantly affected by modifications at R2 and K4. In vitro kinetic studies, using epigenetically modified short N-terminal peptides mimicking histone H3, could provide important information leading to a greater understanding of the relationship between histone H3 N-terminal modification patterns and in vivo kinase activities.