Identification of substrates of an S-phase cell cycle kinase from<i>Leishmania donovani</i>

Maity, Arnab; Goswami, A.; Saha, Partha

doi:10.1016/j.febslet.2011.06.017

Cited by 8 publications

(12 citation statements)

References 22 publications

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“…The increased expression of the CDKs in the ovaries from R. microplus suggests that, as in mammals, these proteins could participate in egg development. The participation of CDKs in the regulation of cell cycle and the formation of the embryo has already been reported in other invertebrates such as C. elegans [50] and Drosophila [51], [52], and the parasite Leishmania donovani [53].…”

Section: Discussionmentioning

confidence: 68%

Identification and Structural-Functional Analysis of Cyclin-Dependent Kinases of the Cattle Tick Rhipicephalus (Boophilus) microplus

Gomes

Romeiro²,

Braz

et al. 2013

PLoS ONE

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Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases essential for cell cycle progression. Herein, we describe the participation of CDKs in the physiology of Rhipicephalus microplus, the southern cattle tick and an important disease vector. Firstly, amino acid sequences homologous with CDKs of other organisms were identified from a R. microplus transcriptome database in silico. The analysis of the deduced amino acid sequences of CDK1 and CDK10 from R. microplus showed that both have caspase-3/7 cleavage motifs despite their differences in motif position and length of encoded proteins. CDK1 has two motifs (DKRGD and SAKDA) located opposite to the ATP binding site while CDK10 has only one motif (SLLDN) for caspase 3–7 near the ATP binding site. Roscovitine (Rosco), a purine derivative that inhibits CDK/cyclin complexes by binding to the catalytic domain of the CDK molecule at the ATP binding site, which prevents the transfer of ATP's γphosphoryl group to the substrate. To determine the effect of Rosco on tick CDKs, BME26 cells derived from R. microplus embryo cells were utilized in vitro inhibition assays. Cell viability decreased in the Rosco-treated groups after 24 hours of incubation in a concentration-dependent manner and this was observed up to 48 hours following incubation. To our knowledge, this is the first report on characterization of a cell cycle protein in arachnids, and the sensitivity of BME26 tick cell line to Rosco treatment suggests that CDKs are potential targets for novel drug design to control tick infestation.

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Section: Discussionmentioning

confidence: 68%

Identification and Structural-Functional Analysis of Cyclin-Dependent Kinases of the Cattle Tick Rhipicephalus (Boophilus) microplus

Gomes

Romeiro²,

Braz

et al. 2013

PLoS ONE

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“…Leishmania donovani CRK3 has also been reported to interact with, and be activated by, Cyc1 (the homolog of CYCA) both in vitro and in vivo, although in this case, Cyc1 was shown to be expressed during S phase [37,38]. The identified in vitro substrates of CRK3:Cyc1 include putative Ku70 and MYST family histone acetyl transferase homologs, which is consistent with an Sphase role for this CDK complex [39]. In contrast, T. cruzi CRK3 was shown to interact with CYC4 and CYC5 in a yeast two-hybrid assay, but not with CYC2 [40].…”

Section: Crk3mentioning

confidence: 70%

Trypanosomatid Cell Division Kinases

Benz

Thomas

Hammarton

2013

Protein Phosphorylation in Parasites

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Advances have been made recently in understanding the order of events in the cell division cycles of Leishmania spp. and Trypanosoma cruzi, adding to previous knowledge of events in Trypanosoma brucei, and highlighting similarities and differences between these trypanosomatids. However, the present understanding of how the cell cycle is regulated by kinases still largely derives from analyses in T. brucei, since convenient genetic tools for analyzing the function of essential regulators -for example, inducible expression systems and/or RNA interferenceare still lacking in Leishmania and T. cruzi. While current understanding of the function of some kinases (e.g., some cyclin-dependent kinases, the NDR kinases, aurora, tousled-like and polo-like kinases) is now very good, many more remain to be characterized, as do details of the signal transduction pathways in which they operate. A number of protein kinases have, in recent years, been genetically -and in some cases also chemically -validated as potential novel drug targets for human African trypanosomiasis or leishmaniasis, although only a few, including CRK3: CYC6, CRK3:CYCA, the NDR kinases, PK50 and PK53 and polo-like kinase, have been subjected to high-throughput screening to identify small-molecule inhibitors. However, problems with these screens include a failure to identify potent inhibitors against the parasite enzyme in vitro, a lack of selectivity for the parasite enzyme over the equivalent human enzyme, or poor efficacy against the parasite. Thus, further chemical investigations will be required to generate new compounds with more ideal properties.

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“…One of the identified substrates of the S‐phase cell cycle kinase LdCyc1‐CRK3 from L. donovani was shown to contain a MYST (human Moz, Yeast Ybf2 and Sas2, and human TIP60) domain of HATs (Maity et al ., ), although further characterization of activity of the protein and its regulation by phosphorylation were not carried out. The HAT protein from L. donovani is 97% identical to LmHAT1, which was grouped with the HAT1 from T. brucei and T. cruzi in a phylogenetic analysis (Kawahara et al ., ).…”

Section: Resultsmentioning

confidence: 99%

The histone acetyl transferase LdHAT1 fromLeishmania donovaniis regulated by S-phase cell cycle kinase

Maity

Saha

2012

FEMS Microbiol Lett

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Histone acetyl transferases (HATs) are important histone modifiers that affect critical cellular processes like transcription, DNA replication and repairs through highly dynamic chromatin remodelling. Our earlier studies recognized LdHAT1 as a substrate of the S-phase cell cycle kinase LdCyc1-CRK3 from Leishmania donovani. Here, we confirm through site-directed mutagenesis that RXL-like cyclin-binding (Cy) motif dependent interaction of LdHAT1 with LdCyc1 is essential for its phosphorylation at a canonical Cdk target site by the kinase complex. LdHAT1 acetylates K10 residue of a peptide derived from L. donovani histone H4 N-terminal tail. Interestingly, phosphorylation of LdHAT1 by the S-phase kinase inhibits its H4K10 acetylation activity, implicating an important mechanism of periodic regulation of histone acetylation during cell cycle progression.

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Identification of substrates of an S-phase cell cycle kinase fromLeishmania donovani

Cited by 8 publications

References 22 publications

Identification and Structural-Functional Analysis of Cyclin-Dependent Kinases of the Cattle Tick Rhipicephalus (Boophilus) microplus

Identification and Structural-Functional Analysis of Cyclin-Dependent Kinases of the Cattle Tick Rhipicephalus (Boophilus) microplus

Trypanosomatid Cell Division Kinases

The histone acetyl transferase LdHAT1 fromLeishmania donovaniis regulated by S-phase cell cycle kinase

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