1887

Abstract

Thorough bioinformatic and phylogenetic analyses of tyrosine kinase-like kinase (TKL) sequences revealed a clear evolutionary relationship of PF3D7_1121300 (thereafter called PfTKL2) to the IL-1 receptor-associated kinase (IRAK)/receptor-like kinase (RLK)/Pelle protein family. We identified a novel conserved motif that is unique to this family, as well as an insertion whose length allows distribution of its members into two distinct subfamilies, in a way that matches exactly the dichotomy between ‘Tube/Tube-like kinases’ (TTLKs) and ‘Pelle-like kinases’ (PLKs) distinguished previously on the basis of features in accessory domains. The PfTKL2 protein is expressed ubiquitously in asexual blood stages and in gametocytes, and the recombinant enzyme displays kinase activity . The protein is exported to the host erythrocyte; furthermore, in accordance with data from a previous study of the extracellular proteome of -infected erythrocytes, we show that PfTKL2 is secreted into the culture medium. Considering the functions of other members of the RLK/Pelle family in immunity, and its secretion to the extracellular medium, we speculate that PfTKL2 functions may include an immunomodulatory role promoting parasite survival in the human host.

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2013-12-01
2019-10-17
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References

  1. Abdi A. , Eschenlauer S. , Reininger L. , Doerig C. . ( 2010; ). SAM domain-dependent activity of PfTKL3, an essential tyrosine kinase-like kinase of the human malaria parasite Plasmodium falciparum . . Cell Mol Life Sci 67:, 3355–3369. [CrossRef] [PubMed]
    [Google Scholar]
  2. Afzal A. J. , Wood A. J. , Lightfoot D. A. . ( 2008; ). Plant receptor-like serine threonine kinases: roles in signaling and plant defense. . Mol Plant Microbe Interact 21:, 507–517. [CrossRef] [PubMed]
    [Google Scholar]
  3. Arnold K. , Bordoli L. , Kopp J. , Schwede T. . ( 2006; ). The swiss-model workspace: a web-based environment for protein structure homology modelling. . Bioinformatics 22:, 195–201. [CrossRef] [PubMed]
    [Google Scholar]
  4. Baker D. , Sali A. . ( 2001; ). Protein structure prediction and structural genomics. . Science 294:, 93–96. [CrossRef] [PubMed]
    [Google Scholar]
  5. Bayer M. , Nawy T. , Giglione C. , Galli M. , Meinnel T. , Lukowitz W. . ( 2009; ). Paternal control of embryonic patterning in Arabidopsis thaliana . . Science 323:, 1485–1488. [CrossRef] [PubMed]
    [Google Scholar]
  6. Berendt A. R. , Simmons D. L. , Tansey J. , Newbold C. I. , Marsh K. . ( 1989; ). Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum . . Nature 341:, 57–59. [CrossRef] [PubMed]
    [Google Scholar]
  7. Blisnick T. , Morales Betoulle M. E. , Barale J. C. , Uzureau P. , Berry L. , Desroses S. , Fujioka H. , Mattei D. , Braun Breton C. . ( 2000; ). Pfsbp1, a Maurer’s cleft Plasmodium falciparum protein, is associated with the erythrocyte skeleton. . Mol Biochem Parasitol 111:, 107–121. [CrossRef] [PubMed]
    [Google Scholar]
  8. Buckley G. M. , Ceska T. A. , Fraser J. L. , Gowers L. , Groom C. R. , Higueruelo A. P. , Jenkins K. , Mack S. R. , Morgan T. . & other authors ( 2008a; ). IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding. . Bioorg Med Chem Lett 18:, 3291–3295. [CrossRef] [PubMed]
    [Google Scholar]
  9. Buckley G. M. , Fosbeary R. , Fraser J. L. , Gowers L. , Higueruelo A. P. , James L. A. , Jenkins K. , Mack S. R. , Morgan T. . & other authors ( 2008b; ). IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines. . Bioorg Med Chem Lett 18:, 3656–3660. [CrossRef] [PubMed]
    [Google Scholar]
  10. Buckley G. M. , Gowers L. , Higueruelo A. P. , Jenkins K. , Mack S. R. , Morgan T. , Parry D. M. , Pitt W. R. , Rausch O. . & other authors ( 2008c; ). IRAK-4 inhibitors. Part 1: a series of amides. . Bioorg Med Chem Lett 18:, 3211–3214. [CrossRef] [PubMed]
    [Google Scholar]
  11. Carter R. , Ranford-Cartwright L. , Alano P. . ( 1993; ). The culture and preparation of gametocytes of Plasmodium falciparum for immunochemical, molecular, and mosquito infectivity studies. . Methods Mol Biol 21:, 67–88.[PubMed]
    [Google Scholar]
  12. Cheng H. , Addona T. , Keshishian H. , Dahlstrand E. , Lu C. , Dorsch M. , Li Z. , Wang A. , Ocain T. D. . & other authors ( 2007; ). Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop. . Biochem Biophys Res Commun 352:, 609–616. [CrossRef] [PubMed]
    [Google Scholar]
  13. Cirl C. , Wieser A. , Yadav M. , Duerr S. , Schubert S. , Fischer H. , Stappert D. , Wantia N. , Rodriguez N. . & other authors ( 2008; ). Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. . Nat Med 14:, 399–406. [CrossRef] [PubMed]
    [Google Scholar]
  14. Cohen P. . ( 2009; ). Targeting protein kinases for the development of anti-inflammatory drugs. . Curr Opin Cell Biol 21:, 317–324. [CrossRef] [PubMed]
    [Google Scholar]
  15. Coulombe P. , Meloche S. . ( 2007; ). Atypical mitogen-activated protein kinases: structure, regulation and functions. . Biochim Biophys Acta 1773:, 1376–1387. [CrossRef] [PubMed]
    [Google Scholar]
  16. Dobson S. E. , Augustijn K. D. , Brannigan J. A. , Schnick C. , Janse C. J. , Dodson E. J. , Waters A. P. , Wilkinson A. J. . ( 2009; ). The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei . . Protein Sci 18:, 2578–2591. [CrossRef] [PubMed]
    [Google Scholar]
  17. Dorin D. , Alano P. , Boccaccio I. , Cicéron L. , Doerig C. , Sulpice R. , Parzy D. , Doerig C. . ( 1999; ). An atypical mitogen-activated protein kinase (MAPK) homologue expressed in gametocytes of the human malaria parasite Plasmodium falciparum. Identification of a MAPK signature. . J Biol Chem 274:, 29912–29920. [CrossRef] [PubMed]
    [Google Scholar]
  18. Dorin-Semblat D. , Carvalho T. , Nivez M. P. , Halbert J. , Poullet P. , Semblat J. P. , Goldring D. , Chakrabarti D. , Mehra P. , Dhar S. , Paing M. P. , Goldberg D. E. , McMillan P. E. , Tilley L. , Doerig C. . ( 2013; ). An atypical cyclin-dependent kinase controls Plasmodium falciparum proliferation rate. . Kinome 1:: 4. [CrossRef] [PubMed]
    [Google Scholar]
  19. Eddy S. R. . ( 1998; ). Profile hidden Markov models. . Bioinformatics 14:, 755–763. [CrossRef] [PubMed]
    [Google Scholar]
  20. Goldberg J. M. , Manning G. , Liu A. , Fey P. , Pilcher K. E. , Xu Y. , Smith J. L. . ( 2006; ). The dictyostelium kinome – analysis of the protein kinases from a simple model organism. . PLoS Genet 2:, e38. [CrossRef] [PubMed]
    [Google Scholar]
  21. Hanks S. K. . ( 2003; ). Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. . Genome Biol 4:, 111. [CrossRef] [PubMed]
    [Google Scholar]
  22. Ho S. N. , Hunt H. D. , Horton R. M. , Pullen J. K. , Pease L. R. . ( 1989; ). Site-directed mutagenesis by overlap extension using the polymerase chain reaction. . Gene 77:, 51–59. [CrossRef] [PubMed]
    [Google Scholar]
  23. Kim T. W. , Staschke K. , Bulek K. , Yao J. , Peters K. , Oh K. H. , Vandenburg Y. , Xiao H. , Qian W. . & other authors ( 2007; ). A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. . J Exp Med 204:, 1025–1036. [CrossRef] [PubMed]
    [Google Scholar]
  24. Klein M. , Dinér P. , Dorin-Semblat D. , Doerig C. , Grøtli M. . ( 2009; ). Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase. . Org Biomol Chem 7:, 3421–3429. [CrossRef] [PubMed]
    [Google Scholar]
  25. Kostich M. , English J. , Madison V. , Gheyas F. , Wang L. , Qiu P. , Greene J. , Laz T. M. . ( 2002; ). Human members of the eukaryotic protein kinase family. . Genome Biol 3:, H0043. [CrossRef] [PubMed]
    [Google Scholar]
  26. Koziczak-Holbro M. , Joyce C. , Glück A. , Kinzel B. , Müller M. , Gram H. . ( 2007a; ). Solving the IRAK-4 enigma: application of kinase-dead knock-in mice. . Ernst Schering Found Symp Proc 63–82. [CrossRef] [PubMed]
    [Google Scholar]
  27. Koziczak-Holbro M. , Joyce C. , Glück A. , Kinzel B. , Müller M. , Tschopp C. , Mathison J. C. , Davis C. N. , Gram H. . ( 2007b; ). IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and Toll-like receptor 7-mediated signaling and gene expression. . J Biol Chem 282:, 13552–13560. [CrossRef] [PubMed]
    [Google Scholar]
  28. Kuglstatter A. , Villaseñor A. G. , Shaw D. , Lee S. W. , Tsing S. , Niu L. , Song K. W. , Barnett J. W. , Browner M. F. . ( 2007; ). Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations. . J Immunol 178:, 2641–2645.[PubMed] [CrossRef]
    [Google Scholar]
  29. Lehti-Shiu M. D. , Zou C. , Hanada K. , Shiu S. H. . ( 2009; ). Evolutionary history and stress regulation of plant receptor-like kinase/Pelle genes. . Plant Physiol 150:, 12–26. [CrossRef] [PubMed]
    [Google Scholar]
  30. Li S. , Strelow A. , Fontana E. J. , Wesche H. . ( 2002; ). IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. . Proc Natl Acad Sci U S A 99:, 5567–5572. [CrossRef] [PubMed]
    [Google Scholar]
  31. Lye E. , Mirtsos C. , Suzuki N. , Suzuki S. , Yeh W. C. . ( 2004; ). The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. . J Biol Chem 279:, 40653–40658. [CrossRef] [PubMed]
    [Google Scholar]
  32. Manning G. , Plowman G. D. , Hunter T. , Sudarsanam S. . ( 2002; ). Evolution of protein kinase signaling from yeast to man. . Trends Biochem Sci 27:, 514–520. [CrossRef] [PubMed]
    [Google Scholar]
  33. Mantovani A. , Bonecchi R. , Locati M. . ( 2006; ). Tuning inflammation and immunity by chemokine sequestration: decoys and more. . Nat Rev Immunol 6:, 907–918. [CrossRef] [PubMed]
    [Google Scholar]
  34. Martí-Renom M. A. , Stuart A. C. , Fiser A. , Sánchez R. , Melo F. , Sali A. . ( 2000; ). Comparative protein structure modeling of genes and genomes. . Annu Rev Biophys Biomol Struct 29:, 291–325. [CrossRef] [PubMed]
    [Google Scholar]
  35. Mens P. F. , Bojtor E. C. , Schallig H. D. . ( 2010; ). Molecular interactions in the placenta during malaria infection. . Eur J Obstet Gynecol Reprod Biol 152:, 126–132. [CrossRef] [PubMed]
    [Google Scholar]
  36. Merckx A. , Echalier A. , Langford K. , Sicard A. , Langsley G. , Joore J. , Doerig C. , Noble M. , Endicott J. . ( 2008; ). Structures of P. falciparum protein kinase 7 identify an activation motif and leads for inhibitor design. . Structure 16:, 228–238. [CrossRef] [PubMed]
    [Google Scholar]
  37. Nicholas K. B. a. N. , Hugh B. jr . ( 1987; ). GeneDoc: a tool for editing and annotating multiple sequence alignments; version 2.6.003. distributed by the author. .
    [Google Scholar]
  38. Ntoukakis V. , Mucyn T. S. , Gimenez-Ibanez S. , Chapman H. C. , Gutierrez J. R. , Balmuth A. L. , Jones A. M. , Rathjen J. P. . ( 2009; ). Host inhibition of a bacterial virulence effector triggers immunity to infection. . Science 324:, 784–787. [CrossRef] [PubMed]
    [Google Scholar]
  39. O’Neill L. A. , Greene C. . ( 1998; ). Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. . J Leukoc Biol 63:, 650–657.[PubMed]
    [Google Scholar]
  40. Qiao X. , He B. , Chiu A. , Knowles D. M. , Chadburn A. , Cerutti A. . ( 2006; ). Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. . Nat Immunol 7:, 302–310. [CrossRef] [PubMed]
    [Google Scholar]
  41. Schofield L. , Grau G. E. . ( 2005; ). Immunological processes in malaria pathogenesis. . Nat Rev Immunol 5:, 722–735. [CrossRef] [PubMed]
    [Google Scholar]
  42. Shao D. , Han Z. , Lin Y. , Zhang L. , Zhong X. , Feng M. , Guo Y. , Wang H. . ( 2008; ). Detection of Plasmodium falciparum derived macrophage migration inhibitory factor homologue in the sera of malaria patients. . Acta Trop 106:, 9–15. [CrossRef] [PubMed]
    [Google Scholar]
  43. Shelton C. A. , Wasserman S. A. . ( 1993; ). pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. . Cell 72:, 515–525. [CrossRef] [PubMed]
    [Google Scholar]
  44. Shiu S. H. , Bleecker A. B. . ( 2001; ). Receptor-like kinases from Arabidopsis form a monophyletic gene family related to animal receptor kinases. . Proc Natl Acad Sci U S A 98:, 10763–10768. [CrossRef] [PubMed]
    [Google Scholar]
  45. Shiu S. H. , Bleecker A. B. . ( 2003; ). Expansion of the receptor-like kinase/Pelle gene family and receptor-like proteins in Arabidopsis . . Plant Physiol 132:, 530–543. [CrossRef] [PubMed]
    [Google Scholar]
  46. Singh M. , Mukherjee P. , Narayanasamy K. , Arora R. , Sen S. D. , Gupta S. , Natarajan K. , Malhotra P. . ( 2009; ). Proteome analysis of Plasmodium falciparum extracellular secretory antigens at asexual blood stages reveals a cohort of proteins with possible roles in immune modulation and signaling. . Mol Cell Proteomics 8:, 2102–2118. [CrossRef] [PubMed]
    [Google Scholar]
  47. Smith P. , Fallon R. E. , Mangan N. E. , Walsh C. M. , Saraiva M. , Sayers J. R. , McKenzie A. N. , Alcami A. , Fallon P. G. . ( 2005; ). Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. . J Exp Med 202:, 1319–1325. [CrossRef] [PubMed]
    [Google Scholar]
  48. Sun T. , Holowka T. , Song Y. , Zierow S. , Leng L. , Chen Y. , Xiong H. , Griffith J. , Nouraie M. . & other authors ( 2012; ). A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria. . Proc Natl Acad Sci U S A 109:, E2117–E2126. [CrossRef] [PubMed]
    [Google Scholar]
  49. Tamura K. , Dudley J. , Nei M. , Kumar S. . ( 2007; ). mega4: molecular evolutionary genetics analysis (MEGA) software version 4.0. . Mol Biol Evol 24:, 1596–1599. [CrossRef] [PubMed]
    [Google Scholar]
  50. Tewari R. , Straschil U. , Bateman A. , Böhme U. , Cherevach I. , Gong P. , Pain A. , Billker O. . ( 2010; ). The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission. . Cell Host Microbe 8:, 377–387. [CrossRef] [PubMed]
    [Google Scholar]
  51. Thorat S. , Daly T. M. , Bergman L. W. , Burns J. M. Jr . ( 2010; ). Elevated levels of the Plasmodium yoelii homologue of macrophage migration inhibitory factor attenuate blood-stage malaria. . Infect Immun 78:, 5151–5162. [CrossRef] [PubMed]
    [Google Scholar]
  52. Tonkin C. J. , van Dooren G. G. , Spurck T. P. , Struck N. S. , Good R. T. , Handman E. , Cowman A. F. , McFadden G. I. . ( 2004; ). Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method. . Mol Biochem Parasitol 137:, 13–21. [CrossRef] [PubMed]
    [Google Scholar]
  53. Towb P. , Sun H. , Wasserman S. A. . ( 2009; ). Tube is an IRAK-4 homolog in a Toll pathway adapted for development and immunity. . J Innate Immun 1:, 309–321. [CrossRef] [PubMed]
    [Google Scholar]
  54. Wang Z. , Liu J. , Sudom A. , Ayres M. , Li S. , Wesche H. , Powers J. P. , Walker N. P. . ( 2006; ). Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. . Structure 14:, 1835–1844. [CrossRef] [PubMed]
    [Google Scholar]
  55. Wang Z. , Wesche H. , Stevens T. , Walker N. , Yeh W. C. . ( 2009; ). IRAK-4 inhibitors for inflammation. . Curr Top Med Chem 9:, 724–737. [CrossRef] [PubMed]
    [Google Scholar]
  56. Ward P. , Equinet L. , Packer J. , Doerig C. . ( 2004; ). Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. . BMC Genomics 5:, 79. [CrossRef] [PubMed]
    [Google Scholar]
  57. Xing W. , Zou Y. , Liu Q. , Liu J. , Luo X. , Huang Q. , Chen S. , Zhu L. , Bi R. . & other authors ( 2007; ). The structural basis for activation of plant immunity by bacterial effector protein AvrPto. . Nature 449:, 243–247. [CrossRef] [PubMed]
    [Google Scholar]
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