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Inhibition of the SR Protein-Phosphorylating CLK Kinases of Plasmodium falciparum Impairs Blood Stage Replication and Malaria Transmission

Please always quote using this URN: urn:nbn:de:bvb:20-opus-115405
  • Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified threeCyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-beta-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.show moreshow less

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Metadaten
Author: Selina Kern, Shruti Agarwal, Kilian Huber, Andre P. Gehring, Benjamin Strödke, Christine C. Wirth, Thomas Brügl, Liane Onambele Abodo, Thomas Dandekar, Christian Doerig, Rainer Fischer, Andrew B. Tobin, Mahmood M. Alam, Franz Bracher, Gabriele Pradel
URN:urn:nbn:de:bvb:20-opus-115405
Document Type:Journal article
Faculties:Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):PLOS ONE
ISSN:1932-6203
Year of Completion:2014
Volume:9
Issue:9
Pagenumber:e105732
Source:PLoS ONE 9(9): e105732. doi:10.1371/journal.pone.0105732
DOI:https://doi.org/10.1371/journal.pone.0105732
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25188378
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Tag:RNA-SEQ; culture; expression; identification; in-vitro; lactate dehydrogenase; mosquito; parasite; splicing factors; xanthurenic acid
Release Date:2015/07/14
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung