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 Amber Siddiqui,Shailja Singh,Sharad Mistry,Maria Viskaduraki,Kate D. Lee,Christine S. Hopp,Chetan E. Chitnis,Christian Doerig,Robert W. Moon,Judith L. Green,Anthony A. Holder,David A. Baker,Andrew B. Tobin +16 more
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TLDR
The phosphorylation sites on 69 proteins involved in cell signalling, proteolysis, gene regulation, protein export and ion and protein transport are identified, indicating that cGMP/PfPKG acts as a signalling hub that plays a central role in a number of core parasite processes.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.read more
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The Molecular Basis of Erythrocyte Invasion by Malaria Parasites
Alan F. Cowman,Alan F. Cowman,Christopher J. Tonkin,Christopher J. Tonkin,Wai-Hong Tham,Wai-Hong Tham,Manoj T. Duraisingh +6 more
TL;DR: The latest in the understanding of the molecular composition of this highly complex and fascinating biological process of Plasmodium species cause malaria is reviewed.
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Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii.
TL;DR: An auxin-inducible degron (AID) tagging system for conditional protein depletion in T. gondii and a conditional protein regulation tool to interrogate PKG isoforms determined that PKGI is necessary and fully sufficient for PKG-dependent cellular processes, whereas PKGII is functionally insufficient and dispensable in the presence of PKGI.
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The structure of the core NuRD repression complex provides insights into its interaction with chromatin
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A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.
David A. Baker,Lindsay B. Stewart,Jonathan M. Large,Paul W. Bowyer,Keith H. Ansell,María Belén Jiménez-Díaz,Majida El Bakkouri,Majida El Bakkouri,Kristian Birchall,Koen J. Dechering,Nathalie Bouloc,P.J. Coombs,David Whalley,Denise J. Harding,Ela Smiljanic-Hurley,Mary C. Wheldon,Eloise M. Walker,Johannes T. Dessens,Maria Lafuente,Laura Sanz,Francisco-Javier Gamo,Santiago Ferrer,Raymond Hui,Raymond Hui,Teun Bousema,Iñigo Angulo-Barturen,Andy Merritt,Simon L. Croft,Winston E. Gutteridge,Catherine A. Kettleborough,Simon A. Osborne +30 more
TL;DR: An imidazopyridine series is generated that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes and warrants consideration for further development to produce an antimalarial drug.
References
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