Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion

Mahmood M. Alam, Lev Solyakov, Andrew R. Bottrill, Christian Flueck, Faiza A. Siddiqui, Shailja Singh, Sharad Mistry, Maria Viskaduraki, Kate Lee, Christine S. Hopp, Chetan E. Chitnis, Christian Doerig, Robert W. Moon, Judith L. Green, Anthony A. Holder, David A. Baker () and Andrew B. Tobin ()
Additional contact information
Mahmood M. Alam: MRC Toxicology Unit, University of Leicester, Hodgkin Building
Lev Solyakov: MRC Toxicology Unit, University of Leicester, Hodgkin Building
Andrew R. Bottrill: PNACL, Core Biotechnology Services, University of Leicester
Christian Flueck: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine
Faiza A. Siddiqui: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Shailja Singh: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Sharad Mistry: PNACL, Core Biotechnology Services, University of Leicester
Maria Viskaduraki: Bioinformatics and Biostatistics Support Hub (B/BASH), Core Biotechnology Services, Maurice Shock Building, University of Leicester
Kate Lee: Bioinformatics and Biostatistics Support Hub (B/BASH), Core Biotechnology Services, Maurice Shock Building, University of Leicester
Christine S. Hopp: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine
Chetan E. Chitnis: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Christian Doerig: Monash University, Building 76
Robert W. Moon: MRC National Institute for Medical Research
Judith L. Green: MRC National Institute for Medical Research
Anthony A. Holder: MRC National Institute for Medical Research
David A. Baker: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine
Andrew B. Tobin: MRC Toxicology Unit, University of Leicester, Hodgkin Building

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Our understanding of the key phosphorylation-dependent signalling pathways in the human malaria parasite, Plasmodium falciparum, remains rudimentary. Here we address this issue for the essential cGMP-dependent protein kinase, PfPKG. By employing chemical and genetic tools in combination with quantitative global phosphoproteomics, we identify the phosphorylation sites on 69 proteins that are direct or indirect cellular targets for PfPKG. These PfPKG targets include proteins involved in cell signalling, proteolysis, gene regulation, protein export and ion and protein transport, indicating that cGMP/PfPKG acts as a signalling hub that plays a central role in a number of core parasite processes. We also show that PfPKG activity is required for parasite invasion. This correlates with the finding that the calcium-dependent protein kinase, PfCDPK1, is phosphorylated by PfPKG, as are components of the actomyosin complex, providing mechanistic insight into the essential role of PfPKG in parasite egress and invasion.

Date: 2015
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DOI: 10.1038/ncomms8285

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