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FIKK kinases in the human malaria parasite Plasmodium falciparum are attractive targets for new anti-malaria drugs, as they have no orthologues in humans and have been linked to disease severity. Six FIKKs are known to be exported into red blood cells (RBCs) where they mediate dramatic structural and functional changes to RBCs that are central to pathogenesis. Eleven members of this family, which are predicted to be exported into infected RBCs (iRBCs), remain uncharacterised. Using a targeted gene-knockout approach, we have characterised these FIKKs and discovered that five are essential for parasite survival. Three of these five FIKKs (FIKK9.1, FIKK10.1, FIKK10.2) were exported from the parasite into iRBCs and for two of these (FIKK9.1 and FIKK10.1), export was via Maurer's clefts (parasite-derived structures involved in protein trafficking and pathognomonic of falciparum malaria). Of the remaining two essential kinases, FIKK3 was associated with rhoptries (specialised protein secretory organelles in the parasite) and FIKK9.5 was localised in the parasite nucleus. The diverse localisation and essentiality of these FIKKs demonstrate that they play different but essential roles in the survival of P. falciparum in RBCs and therefore are attractive new drug targets for the prevention or treatment of falciparum malaria.

Titel:	Identification of essential exported Plasmodium falciparum protein kinases in malaria-infected red blood cells.
Autor/in / Beteiligte Person:	Siddiqui, G ; Proellochs, NI ; Cooke, BM
Zeitschrift:	British journal of haematology, Jg. 188 (2020-03-01), Heft 5, S. 774-783
Veröffentlichung:	Oxford : Wiley-Blackwell ; <i>Original Publication</i>: Oxford : Blackwell Scientific Publications, 2020
Medientyp:	academicJournal
ISSN:	1365-2141 (electronic)
DOI:	10.1111/bjh.16219
Schlagwort:	Erythrocytes parasitology Erythrocytes pathology Humans Malaria, Falciparum genetics Malaria, Falciparum pathology Plasmodium falciparum genetics Protein Kinases genetics Protozoan Proteins genetics Erythrocytes enzymology Malaria, Falciparum enzymology Plasmodium falciparum enzymology Protein Kinases metabolism Protozoan Proteins metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Br J Haematol] 2020 Mar; Vol. 188 (5), pp. 774-783. <i>Date of Electronic Publication: </i>2019 Oct 24. MeSH Terms: Erythrocytes / enzymology ; Malaria, Falciparum / enzymology ; Plasmodium falciparum / enzymology ; Protein Kinases / metabolism ; Protozoan Proteins / *metabolism ; Erythrocytes / parasitology ; Erythrocytes / pathology ; Humans ; Malaria, Falciparum / genetics ; Malaria, Falciparum / pathology ; Plasmodium falciparum / genetics ; Protein Kinases / genetics ; Protozoan Proteins / genetics Comments: Comment in: Br J Haematol. 2020 Mar;188(5):603-604. (PMID: 31566726) References: Anamika, K., Srinivasan, N. & Krupa, A. (2005) A genomic perspective of protein kinases in Plasmodium falciparum. Proteins, 58, 180-189. ; Bannister, L.H., Hopkins, J.M., Fowler, R.E., Krishna, S. & Mitchell, G.H. 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Grant Information: 790085.c International European Union's Horizon 2020 Research and Innovation Programme Contributed Indexing: Keywords: Plasmodium falciparum; FIKK kinases; drug targets; kinases; malaria; red blood cells Substance Nomenclature: 0 (Protozoan Proteins) ; EC 2.7.- (Protein Kinases) Entry Date(s): Date Created: 20191026 Date Completed: 20201013 Latest Revision: 20201013 Update Code: 20240513

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Identification of essential exported Plasmodium falciparum protein kinases in malaria-infected red blood cells.