Abstract
BackgroundThe Apicomplexa constitute an evolutionarily divergent phylum of protozoan pathogens responsible for widespread parasitic diseases such as malaria and toxoplasmosis. Many cellular functions in these medically important organisms are controlled by protein kinases, which have emerged as promising drug targets for parasitic diseases. However, an incomplete understanding of how apicomplexan kinases structurally and mechanistically differ from their host counterparts has hindered drug development efforts to target parasite kinases.ResultsWe used the wealth of sequence data recently made available for 15 apicomplexan species to identify the kinome of each species and quantify the evolutionary constraints imposed on each family of apicomplexan kinases. Our analysis revealed lineage-specific adaptations in selected families, namely cyclin-dependent kinase (CDK), calcium-dependent protein kinase (CDPK) and CLK/LAMMER, which have been identified as important in the pathogenesis of these organisms. Bayesian analysis of selective constraints imposed on these families identified the sequence and structural features that most distinguish apicomplexan protein kinases from their homologs in model organisms and other eukaryotes. In particular, in a subfamily of CDKs orthologous to Plasmodium falciparum crk-5, the activation loop contains a novel PTxC motif which is absent from all CDKs outside Apicomplexa. Our analysis also suggests a convergent mode of regulation in a subset of apicomplexan CDPKs and mammalian MAPKs involving a commonly conserved arginine in the αC helix. In all recognized apicomplexan CLKs, we find a set of co-conserved residues involved in substrate recognition and docking that are distinct from metazoan CLKs.ConclusionsWe pinpoint key conserved residues that can be predicted to mediate functional differences from eukaryotic homologs in three identified kinase families. We discuss the structural, functional and evolutionary implications of these lineage-specific variations and propose specific hypotheses for experimental investigation. The apicomplexan-specific kinase features reported in this study can be used in the design of selective kinase inhibitors.
Highlights
The Apicomplexa constitute an evolutionarily divergent phylum of protozoan pathogens responsible for widespread parasitic diseases such as malaria and toxoplasmosis
We identified and classified the eukaryotic protein kinases in a total of 17 genomes from 15 species, as well as the solved apicomplexan ePK structures in the Protein Data Bank [34]
Orthologs of Pfcrk-5 form a novel subfamily of cyclindependent kinases While each apicomplexan kinome contains multiple genes belonging to the cyclin-dependent kinase (CDK) family, we find a novel CDK subfamily which appears in a single copy in 14 of the 17 apicomplexan genomes surveyed, absent only from Cryptosporidium spp., and is not found outside Apicomplexa
Summary
The Apicomplexa constitute an evolutionarily divergent phylum of protozoan pathogens responsible for widespread parasitic diseases such as malaria and toxoplasmosis. In recent years, understanding of the molecular biology and evolution of this phylum has improved dramatically; yet effective treatments for these diseases are still elusive, Several traits make these pathogens difficult to target therapeutically As eukaryotes, they share a number of pathways with their mammalian and avian hosts; as intracellular parasites, they have been observed to quickly develop resistance to pharmaceutical treatments [3]. Several analyses of protein kinases in these organisms, in particular, have pointed out key signaling pathways [18,19,20], instances of expansion and loss of kinase gene families [21,22], and emergence of novel protein kinase families [21,23,24], providing important insights into biological functions. These comparative studies have proposed hypotheses which have subsequently been validated by functional and structural studies [19,20,25,26]
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