An evolutionary perspective on the kinome of malaria parasites

Talevich, Eric; Tobin, Andrew B.; Kannan, Natarajan; Doerig, Christian

doi:10.1098/rstb.2012.0014

Cited by 60 publications

(62 citation statements)

References 109 publications

(177 reference statements)

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“…The calcium-dependent protein kinases (CDPKs) comprise a large family of Ca 2þ regulated kinases found in plants [13] and alveolates [38] (see Talevich et al [191], in this issue) that have a domain similar to calmodulin and bind Ca 2þ directly. Different CDPKs bind to Ca 2þ with differing affinities, potentially allowing different CDPKs to respond to different Ca 2þ signals [20].…”

Section: Cdpkmentioning

confidence: 99%

Diversity, classification and function of the plant protein kinase superfamily

Lehti-Shiu

Shiu

2012

Phil. Trans. R. Soc. B

288

374

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Eukaryotic protein kinases belong to a large superfamily with hundreds to thousands of copies and are components of essentially all cellular functions. The goals of this study are to classify protein kinases from 25 plant species and to assess their evolutionary history in conjunction with consideration of their molecular functions. The protein kinase superfamily has expanded in the flowering plant lineage, in part through recent duplications. As a result, the flowering plant protein kinase repertoire, or kinome, is in general significantly larger than other eukaryotes, ranging in size from 600 to 2500 members. This large variation in kinome size is mainly due to the expansion and contraction of a few families, particularly the receptor-like kinase/Pelle family. A number of protein kinases reside in highly conserved, low copy number families and often play broadly conserved regulatory roles in metabolism and cell division, although functions of plant homologues have often diverged from their metazoan counterparts. Members of expanded plant kinase families often have roles in plant-specific processes and some may have contributed to adaptive evolution. Nonetheless, non-adaptive explanations, such as kinase duplicate subfunctionalization and insufficient time for pseudogenization, may also contribute to the large number of seemingly functional protein kinases in plants.

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Section: Cdpkmentioning

confidence: 99%

Diversity, classification and function of the plant protein kinase superfamily

Lehti-Shiu

Shiu

2012

Phil. Trans. R. Soc. B

288

374

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“…Similar to other eukaryotic cells, apicomplexan parasites contain a diverse array of protein kinases that are important for regulating their complex biology. Apicomplexans contain many members of the major protein kinase families such as AGC (containing protein kinases A, G, and C), CMGC (containing cyclin-dependent, mitogen-activated, and cell division cycle [CDC]-like kinases), calmodulin kinases (CaMK), and casein kinases (CK) (3,4). Curiously, apicomplexans lack some common kinases like protein kinase C and canonical tyrosine kinases and have reduced number of mitogen-activated protein kinases (3,4).…”

mentioning

confidence: 99%

“…Apicomplexans contain many members of the major protein kinase families such as AGC (containing protein kinases A, G, and C), CMGC (containing cyclin-dependent, mitogen-activated, and cell division cycle [CDC]-like kinases), calmodulin kinases (CaMK), and casein kinases (CK) (3,4). Curiously, apicomplexans lack some common kinases like protein kinase C and canonical tyrosine kinases and have reduced number of mitogen-activated protein kinases (3,4). They also contain several parasite-specific kinases that are expanded, for example, the FIKK (phenylalanine [F] (5,6) and the rhoptry kinases (ROP) implicated in Toxoplasma gondii virulence (7,8).…”

mentioning

confidence: 99%

Analysis of Noncanonical Calcium-Dependent Protein Kinases in Toxoplasma gondii by Targeted Gene Deletion Using CRISPR/Cas9

2016

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Calcium-dependent protein kinases (CDPKs) are expanded in apicomplexan parasites, especially in Toxoplasma gondii where 14 separate genes encoding these enzymes are found. Although previous studies have shown that several CDPKs play a role in controlling invasion, egress, and cell division in T. gondii, the roles of most of these genes are unexplored. Here we developed a more efficient method for gene disruption using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPRassociated protein 9) that was modified to completely delete large, multiexonic genes from the genome and to allow serial replacement by recycling of the selectable marker using Cre-loxP. Using this system, we generated a total of 24 mutants in type 1 and 2 genetic backgrounds to ascertain the functions of noncanonical CDPKs. Remarkably, although we were able to confirm the essentiality of CDPK1 and CDPK7, the majority of CDPKs had no discernible phenotype for growth in vitro or infection in the mouse model. The exception to this was CDPK6, loss of which leads to reduced plaquing, fitness defect in a competition assay, and reduced tissue cyst formation in chronically infected mice. Our findings highlight the utility of CRISPR/Cas9 for rapid serial gene deletion and also suggest that additional models are needed to reveal the functions of many genes in T. gondii.

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“…The STEs are poorly represented in apicomplexans, and although most apicomplexans have one or two STE genes per genome, some parasites such as C. parvum are reported to harbor up to six STEs [15,17]. Our results suggest that S. neurona has at least one putative STE ( Table 1).…”

Section: The Ste Groupmentioning

confidence: 73%

<em>Sarcocystis neurona</em> Protein Kinases: Computational Identification, Evolutionary Analysis and Putative Inhibitor Docking

Murungi

Kariithi

2017

Preprint

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Abstract:The apicomplexan parasite, Sarcocystis neurona causes the degenerative neurological equine protozoal myeloencephalitis (EPM) disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions such as host cell invasion, cell cycle progression and host immune responses evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. Further, three-dimensional (3D) homology models for selected S. neurona putative PKs were constructed and evaluated for inhibitor docking. We identified 92 putative PKs clustering within the AGC, CAMK, CK1, CMGC, STE, TKL, aPK and OPK groups. Although containing the universally conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC, but contained the six apicomplexan conserved CDPKs (CAMK group). The OPK group was represented by ROPKs 19A, 27, 30, 33, 35 and 37, but was devoid of the virulence-associated ROPKs 5, 6, 18 and 38. Two out of the three S. neurona CK1 enzymes had high sequence similarities to T. gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Docking of four inhibitors onto homology models of putative ROP27 and PKA indicated that inhibition of S. neurona PKs is feasible, but needs to be experimentally tested. The essentiality of apicomplexan PKs makes the elucidation of S. neurona kinome a key milestone for development of novel therapeutics for EPM.

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An evolutionary perspective on the kinome of malaria parasites

Cited by 60 publications

References 109 publications

Diversity, classification and function of the plant protein kinase superfamily

Diversity, classification and function of the plant protein kinase superfamily

Analysis of Noncanonical Calcium-Dependent Protein Kinases in Toxoplasma gondii by Targeted Gene Deletion Using CRISPR/Cas9

<em>Sarcocystis neurona</em> Protein Kinases: Computational Identification, Evolutionary Analysis and Putative Inhibitor Docking

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