Abstract
BackgroundLeishmania parasites undergo profound morphological and biochemical changes while passing through their life cycle. Protein kinases have been shown to be involved in the differentiation from the extracellular flagellated promastigotes to the intracellular "non-flagellated" amastigotes and vice versa. Moreover, these enzymes are likely involved in the regulation of the proliferation of the different life stages.ResultsHere, we characterize LmxMPK4, a mitogen-activated protein (MAP) kinase homologue from Leishmania mexicana. The kinase reveals all sequence motifs for classification as a MAP kinase. LmxMPK4 proved to be active as a recombinant protein. The kinase is expressed in promastigotes and amastigotes. It was impossible to generate homozygous gene deletion mutants for LmxMPK4 in promastigotes. Moreover, amastigotes bearing only an episomal copy of the gene stably retained LmxMPK4 over a prolonged period without antibiotic pressure in infected mice.ConclusionLmxMPK4 is essential for promastigotes and amastigotes of Leishmania. It shows significant amino acid sequence divergence to mammalian MAP kinases. Thus, LmxMPK4 is a promising new drug target.
Highlights
Leishmania parasites undergo profound morphological and biochemical changes while passing through their life cycle
In higher eukaryotes the core of the Mitogen-activated protein (MAP) kinase signal transduction cascade is comprised of a MAP kinase kinase kinase (MKKK), a MAP kinase kinase (MKK) and a MAP kinase
LmxMPK4 is highly conserved in the different Leishmania species (L. panamensis 98.6%, L. donovani 97.5%, L. infantum 97.5%, and L. major 98.9% amino acid identities) and has homologues in other kinetoplastids, like Trypanosoma brucei
Summary
Leishmania parasites undergo profound morphological and biochemical changes while passing through their life cycle. Protein kinases have been shown to be involved in the differentiation from the extracellular flagellated promastigotes to the intracellular "non-flagellated" amastigotes and vice versa. These enzymes are likely involved in the regulation of the proliferation of the different life stages. Protein kinases are key regulatory molecules in all eukaryotic cells Together with their antagonists the protein phosphatases they form complex networks of mutually activating and silencing molecules. Their activity affects vital processes like differentiation, proliferation, motility, stress response, and apoptosis [1]. The active MKKK phosphorylates a MAP kinase kinase (MKK) on serine and/or threonine residues in its phosphorylation loop. MKKs are dual-specificity kinases which are able to phosphorylate their substrates, the MAP kinases, on a threonine and a tyrosine residue of the conserved TXY motif of the phosphoryla-
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