Characterization of Plasmodium falciparum protein kinase 2

Kato, Kentaro; Sudo, Atsushi; Kobayashi, Kanae; Tohya, Yukinobu; Akashi, Hiroomi

doi:10.1016/j.molbiopara.2008.07.007

Cited by 20 publications

(29 citation statements)

References 41 publications

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“…PF3D7_1238900 ( pk2 ), PF3D7_1136400 (encoding for a tetratrico peptide repeat region; TPR), and PF3D7_1021700. The calcium/calmodulin-dependent protein kinase PK2 was hitherto only investigated in the asexual blood stages of P. falciparum [61,62] and protein expression in gametocytes has not yet been investigated. The gene product of PF3D7_1136400 comprises a TPR domain, which is known to mediate protein-protein interactions and the assembly of multiprotein complexes (reviewed in [63]), but the function of the plasmodial TPR domain protein is not yet known.…”

Section: Resultsmentioning

confidence: 99%

Changes in the transcriptome of the malaria parasite Plasmodium falciparumduring the initial phase of transmission from the human to the mosquito

et al. 2013

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BackgroundThe transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is mediated by dormant sexual precursor cells, the gametocytes, which become activated in the mosquito midgut. Because gametocytes are the only parasite stages able to establish an infection in the mosquito, they play a crucial role in spreading the tropical disease. The human-to-mosquito transmission triggers important molecular changes in the gametocytes, which initiate gametogenesis and prepare the parasite for life-cycle progression in the insect vector.ResultsTo better understand gene regulations during the initial phase of malaria parasite transmission, we focused on the transcriptome changes that occur within the first half hour of parasite development in the mosquito. Comparison of mRNA levels of P. falciparum gametocytes before and 30 min following activation using suppression subtractive hybridization (SSH) identified 126 genes, which changed in expression during gametogenesis. Among these, 17.5% had putative functions in signaling, 14.3% were assigned to cell cycle and gene expression, 8.7% were linked to the cytoskeleton or inner membrane complex, 7.9% were involved in proteostasis and 6.4% in metabolism, 12.7% were cell surface-associated proteins, 11.9% were assigned to other functions, and 20.6% represented genes of unknown function. For 40% of the identified genes there has as yet not been any protein evidence.For a subset of 27 genes, transcript changes during gametogenesis were studied in detail by real-time RT-PCR. Of these, 22 genes were expressed in gametocytes, and for 15 genes transcript expression in gametocytes was increased compared to asexual blood stage parasites. Transcript levels of seven genes were particularly high in activated gametocytes, pointing at functions downstream of gametocyte transmission to the mosquito. For selected genes, a regulated expression during gametogenesis was confirmed on the protein level, using quantitative confocal microscopy.ConclusionsThe obtained transcriptome data demonstrate the regulations of gene expression immediately following malaria parasite transmission to the mosquito. Our findings support the identification of proteins important for sexual reproduction and further development of the mosquito midgut stages and provide insights into the genetic basis of the rapid adaption of Plasmodium to the insect vector.

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Section: Resultsmentioning

confidence: 99%

Changes in the transcriptome of the malaria parasite Plasmodium falciparumduring the initial phase of transmission from the human to the mosquito

et al. 2013

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“…From kinase domain homology, a prototypical CaMK enzyme may include cgd6_520 which was initially identified as a Cp CRK (CDPK-related kinase) [25]. Although it is 41% identical to and clusters with Pf PK2 (a proven CaMK [26]) in the phylogenetic tree (Figure 2), the auto-inhibitory helix and CaM-binding site of this C. parvum kinase could not be readily identified. Cgd6_3400 clusters on a sister branch to the human CaMK enzymes and is ~40% identical in sequence to them, but the auto-inhibitory helix and CaM-binding motif are not apparent in a sequence analysis.…”

Section: Resultsmentioning

confidence: 99%

The Cryptosporidium parvum Kinome

et al. 2011

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BackgroundHundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the Cryptosporidium parvum kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase.ResultsThe C. parvum kinome comprises over 70 members, some of which may be promising drug targets. These C. parvum protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of Cryptosporidium spp. Comparison of specific kinases with their Plasmodium falciparum and Toxoplasma gondii orthologues revealed some distinct characteristics within the C. parvum kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC50 values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of CpCDPK1. In addition, structural analysis of CpCDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation.ConclusionsIdentification and comparison of the C. parvum protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.

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“…On Ca 2+ binding, calmodulin generally relieves auto‐inhibition of the catalytic domain of calmodulin kinases (CaMK). CaMK are typical of animal cells but are rare in protozoan parasites and only a single classical CaMK was identified in Plasmodium (PfPK2, PF3D7_1238900), which requires both Ca 2+ and calmodulin for its activation (Kato et al ., ).…”

Section: Ca2+ Sensors and Adaptor Proteins In Malaria Parasitesmentioning

confidence: 97%

Calcium signalling in malaria parasites

Brochet

Billker

2016

Molecular Microbiology

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Summary Ca2+ is a ubiquitous intracellular messenger in malaria parasites with important functions in asexual blood stages responsible for malaria symptoms, the preceding liver‐stage infection and transmission through the mosquito. Intracellular messengers amplify signals by binding to effector molecules that trigger physiological changes. The characterisation of some Ca2+ effector proteins has begun to provide insights into the vast range of biological processes controlled by Ca2+ signalling in malaria parasites, including host cell egress and invasion, protein secretion, motility and cell cycle regulation. Despite the importance of Ca2+ signalling during the life cycle of malaria parasites, little is known about Ca2+ homeostasis. Recent findings highlighted that upstream of stage‐specific Ca2+ effectors is a conserved interplay between second messengers to control critical intracellular Ca2+ signals throughout the life cycle. The identification of the molecular mechanisms integrating stage‐transcending mechanisms of Ca2+ homeostasis in a network of stage‐specific regulator and effector pathways now represents a major challenge for a meaningful understanding of Ca2+ signalling in malaria parasites.

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Characterization of Plasmodium falciparum protein kinase 2

Cited by 20 publications

References 41 publications

Changes in the transcriptome of the malaria parasite Plasmodium falciparumduring the initial phase of transmission from the human to the mosquito

Changes in the transcriptome of the malaria parasite Plasmodium falciparumduring the initial phase of transmission from the human to the mosquito

The Cryptosporidium parvum Kinome

Calcium signalling in malaria parasites

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