Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

Lev Solyakov, Jean Halbert, Mahmood M. Alam, Jean-Philippe Semblat, Dominique Dorin-Semblat, Luc Reininger, Andrew R. Bottrill, Sharad Mistry, Abdirhaman Abdi, Clare Fennell, Zoe Holland, Claudia Demarta, Yvan Bouza, Audrey Sicard, Marie-Paule Nivez, Sylvain Eschenlauer, Tenzing Lama, Divya Catherine Thomas, Pushkar Sharma, Shruti Agarwal, Selina Kern, Gabriele Pradel, Michele Graciotti, Andrew B. Tobin () and Christian Doerig ()
Additional contact information
Lev Solyakov: University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Jean Halbert: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Mahmood M. Alam: University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Jean-Philippe Semblat: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Dominique Dorin-Semblat: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Luc Reininger: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Andrew R. Bottrill: Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Sharad Mistry: Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Abdirhaman Abdi: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Clare Fennell: Wellcome Trust Centre for Molecular Parasitology, University of Glasgow
Zoe Holland: Wellcome Trust Centre for Molecular Parasitology, University of Glasgow
Claudia Demarta: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Yvan Bouza: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Audrey Sicard: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Marie-Paule Nivez: Wellcome Trust Centre for Molecular Parasitology, University of Glasgow
Sylvain Eschenlauer: Wellcome Trust Centre for Molecular Parasitology, University of Glasgow
Tenzing Lama: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.
Divya Catherine Thomas: EGE Laboratory, National Institute of Immunology
Pushkar Sharma: EGE Laboratory, National Institute of Immunology
Shruti Agarwal: Research Center for Infectious Diseases, University of Würzburg, Josef-Schneider-Strasse 2/D15, Würzburg 97080, Germany.
Selina Kern: Research Center for Infectious Diseases, University of Würzburg, Josef-Schneider-Strasse 2/D15, Würzburg 97080, Germany.
Gabriele Pradel: Research Center for Infectious Diseases, University of Würzburg, Josef-Schneider-Strasse 2/D15, Würzburg 97080, Germany.
Michele Graciotti: University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Andrew B. Tobin: University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Christian Doerig: Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.

Nature Communications, 2011, vol. 2, issue 1, 1-12

Abstract: Abstract The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.

Date: 2011
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DOI: 10.1038/ncomms1558

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