@article{WagnerVolkmerSharanetal.2014,
  author    = {Wagner, Ines and Volkmer, Michael and Sharan, Malvika and Villaveces, Jose M. and Oswald, Felix and Surendranath, Vineeth and Habermann, Bianca H.},
  title     = {morFeus: a web-based program to detect remotely conserved orthologs using symmetrical best hits and orthology network scoring},
  series = {BMC Bioinformatics},
  volume    = {15},
  journal   = {BMC Bioinformatics},
  number    = {263},
  doi       = {10.1186/1471-2105-15-263},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115590},
  year      = {2014},
  abstract  = {Background: Searching the orthologs of a given protein or DNA sequence is one of the most important and most commonly used Bioinformatics methods in Biology. Programs like BLAST or the orthology search engine Inparanoid can be used to find orthologs when the similarity between two sequences is sufficiently high. They however fail when the level of conservation is low. The detection of remotely conserved proteins oftentimes involves sophisticated manual intervention that is difficult to automate. Results: Here, we introduce morFeus, a search program to find remotely conserved orthologs. Based on relaxed sequence similarity searches, morFeus selects sequences based on the similarity of their alignments to the query, tests for orthology by iterative reciprocal BLAST searches and calculates a network score for the resulting network of orthologs that is a measure of orthology independent of the E-value. Detecting remotely conserved orthologs of a protein using morFeus thus requires no manual intervention. We demonstrate the performance of morFeus by comparing it to state-of-the-art orthology resources and methods. We provide an example of remotely conserved orthologs, which were experimentally shown to be functionally equivalent in the respective organisms and therefore meet the criteria of the orthology-function conjecture. Conclusions: Based on our results, we conclude that morFeus is a powerful and specific search method for detecting remotely conserved orthologs.},
  language  = {en}
}
@article{KernAgarwalHuberetal.2014,
  author    = {Kern, Selina and Agarwal, Shruti and Huber, Kilian and Gehring, Andre P. and Str{\"o}dke, Benjamin and Wirth, Christine C. and Br{\"u}gl, Thomas and Abodo, Liane Onambele and Dandekar, Thomas and Doerig, Christian and Fischer, Rainer and Tobin, Andrew B. and Alam, Mahmood M. and Bracher, Franz and Pradel, Gabriele},
  title     = {Inhibition of the SR Protein-Phosphorylating CLK Kinases of Plasmodium falciparum Impairs Blood Stage Replication and Malaria Transmission},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {9},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0105732},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115405},
  pages     = {e105732},
  year      = {2014},
  abstract  = {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 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.},
  language  = {en}
}