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Nat Commun. 2015 Jul 7;6:7285. doi: 10.1038/ncomms8285.

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

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MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
PNACL, Core Biotechnology Services, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Faculty of Infectious and Tropical Diseases, London School of Hygiene &Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110 067, India.
Bioinformatics and Biostatistics Support Hub (B/BASH), Core Biotechnology Services, Maurice Shock Building, University of Leicester, University Road, Leicester LE1 9HN, UK.
Department of Microbiology, Monash University, Building 76, Clayton, Victoria 3800, Australia.
Division of Parasitology, MRC National Institute for Medical Research, Ridgeway, Mill Hill, London NW7 1AA, UK.


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.

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