title: A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes.
abstract: Clinical malaria is associated with the proliferation of Plasmodium parasites in human erythrocytes. The coordinated processes of parasite egress from and invasion into erythrocytes are rapid and tightly regulated. We have found that the plant-like calcium-dependent protein kinase PfCDPK5, which is expressed in invasive merozoite forms of Plasmodium falciparum, was critical for egress. Parasites deficient in PfCDPK5 arrested as mature schizonts with intact membranes, despite normal maturation of egress proteases and invasion ligands. Merozoites physically released from stalled schizonts were capable of invading new erythrocytes, separating the pathways of egress and invasion. The arrest was downstream of cyclic guanosine monophosphate-dependent protein kinase (PfPKG) function and independent of protease processing. Thus, PfCDPK5 plays an essential role during the blood stage of malaria replication.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Dvorin
authors.forename: Derek C
authors.initials: DC
authors.lastname: Martyn
authors.forename: Saurabh D
authors.initials: SD
authors.lastname: Patel
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Grimley
authors.forename: Christine R
authors.initials: CR
authors.lastname: Collins
authors.forename: Christine S
authors.initials: CS
authors.lastname: Hopp
authors.forename: A Taylor
authors.initials: AT
authors.lastname: Bright
authors.forename: Scott
authors.initials: S
authors.lastname: Westenberger
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Winzeler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wandless
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D008024:Ligands; D052940:Merozoites / Q000201:enzymology / Q000502:physiology; D008954:Models, Biological; D009025:Morpholines / Q000378:metabolism; D010963:Plasmodium falciparum / Q000166:cytology / Q000201:enzymology / Q000254:growth & development / Q000502:physiology*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D052939:Schizonts / Q000166:cytology / Q000201:enzymology / Q000502:physiology
chemical_list: C452660:4-(2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl)pyridine; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D015800:Protozoan Proteins; D011725:Pyridines; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; C540198:Shield-1 compound; D011494:Protein Kinases; C549562:CDPK5 protein, Plasmodium falciparum; D017869:Cyclic GMP-Dependent Protein Kinases
references.citation: J Biol Chem. 2001 Apr 13;276(15):12369-77
references.pmid: 11154702
references.citation: EMBO J. 2009 Mar 18;28(6):725-35
references.pmid: 19214190
references.citation: Mol Biochem Parasitol. 1997 Aug;87(2):211-6
references.pmid: 9247932
references.citation: Mol Microbiol. 2006 Feb;59(4):1175-84
references.pmid: 16430692
references.citation: Cell. 2004 May 14;117(4):503-14
references.pmid: 15137943
references.citation: Nat Methods. 2007 Dec;4(12):1003-5
references.pmid: 17994029
references.citation: Nat Rev Mol Cell Biol. 2005 Jul;6(7):555-66
references.pmid: 16072038
references.citation: Cell Host Microbe. 2007 Nov 15;2(5):316-27
references.pmid: 18005753
references.citation: Science. 2009 Jan 23;323(5913):530-3
references.pmid: 19095897
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1554-9
references.pmid: 19164769
references.citation: Science. 2003 Sep 12;301(5639):1503-8
references.pmid: 12893887
references.citation: Eukaryot Cell. 2010 Jan;9(1):37-45
references.pmid: 19915077
references.citation: Cell. 2006 Sep 8;126(5):995-1004
references.pmid: 16959577
references.citation: Cell. 2007 Dec 14;131(6):1072-83
references.pmid: 18083098
references.citation: Science. 2009 May 8;324(5928):794-7
references.pmid: 19342550
references.citation: Bioorg Med Chem Lett. 2008 Nov 15;18(22):5941-4
references.pmid: 18815033
references.citation: J Biol Chem. 1993 Feb 25;268(6):4347-54
references.pmid: 8440720
references.citation: Nat Chem Biol. 2008 Mar;4(3):203-13
references.pmid: 18246061
references.citation: J Biol Chem. 2008 Nov 7;283(45):30980-9
references.pmid: 18768477
references.citation: Nat Chem Biol. 2008 Jun;4(6):347-56
references.pmid: 18454143
references.citation: Mol Microbiol. 2004 Nov;54(3):676-91
references.pmid: 15491359
references.citation: Nat Methods. 2007 Dec;4(12):1007-9
references.pmid: 17994030