Specific DNA-binding by Apicomplexan AP2 transcription factors

Abstract

Malaria remains one of the most prevalent infectious diseases worldwide, affecting more than half a billion people annually. Despite many years of research, the mechanisms underlying transcriptional regulation in the malaria-causing Plasmodium spp., and in Apicomplexan parasites generally, remain poorly understood. In Plasmodium, few regulatory elements sufficient to drive gene expression have been characterized, and their cognate DNAbinding proteins remain unknown. This study characterizes the DNA-binding specificities of two members of the recently identified Apicomplexan AP2 (ApiAP2) family of putative transcriptional regulators from Plasmodium falciparum. The ApiAP2 proteins contain AP2 domains homologous to the well characterized plant AP2 family of transcriptional regulators, which play key roles in development and environmental stress response pathways. We assayed ApiAP2 protein-DNA interactions using protein-binding microarrays and combined these results with computational predictions of coexpressed target genes to couple these putative trans factors to corresponding cis-regulatory motifs in Plasmodium. Furthermore, we show that protein-DNA sequence specificity is conserved in orthologous proteins between phylogenetically distant Apicomplexan species. The identification of the DNA-binding specificities for ApiAP2 proteins lays the foundation for the exploration of their role as transcriptional regulators during all stages of parasite development. Because of their origin in the plant lineage, ApiAP2 proteins have no homologues in the human host and may prove to be ideal antimalarial targets.gene expression ͉ malaria ͉ Plasmodium ͉ protein-DNA interaction ͉ protein-binding microarray

Phosphorylation of eukaryotic initiation factor-2α promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondii

“…We note that Toxoplasma does not possess basic leucine zipper transcription factors, such as ATF4, which are preferentially translated in response to eIF2α phosphorylation in mammalian cells (19,20). Presently, the only transcription factors identified in Apicomplexa resemble the AP2 domain family described in plants (21,22). It is inviting to speculate that alternative regulators, such as the AP2 factors, may be the targets for preferential translation in these parasites.…”

The transcriptome of Plasmodium vivax reveals divergence and diversity of transcriptional regulation in malaria parasites

“…correlate gene expression data in TP1-9 in P. vivax to the expression data in TP 9,13,17,20,23,29,35,40, and 43 in the P. falciparum transcriptome (Fig. S2).…”

“…This is consistent with the observed delay in expression of a number of DNA replication factors during the P. vivax IDC (Table S2). Proteins containing the AP2-integrase, DNA-binding domain have been recently implicated in the global regulation of the Plasmodium life cycle (34,35). All 22 P. falciparum AP2 proteins have syntenic homologues in P. vivax, of which 19 exhibit identical IDC expression profiles between these two species; one homologue (Pv118015) is shifted from the trophozoite stage in P. falciparum to the late schizont stage in P. vivax, and two homologues (Pv086035 and Pv094580) were below the detection threshold of the P. vivax microarray.…”

Toxoplasma Transcription Factor TgAP2XI-5 Regulates the Expression of Genes Involved in Parasite Virulence and Host Invasion

“…Region 2 was adjacent to and directly upstream of the AP2 domain and appeared to be highly conserved between T. gondii and N. caninum (100% identity), with moderate conservation between T. gondii and either P. falciparum or P. berghei (64% identity for both). In numerous apicomplexan AP2 transcription factors, the region directly upstream of the AP2 domain contains a small DNA-binding motif called the AT-hook (6, 18), but it is unclear whether region 2 of TgAP2XI-5 and its homologs is a true AT-hook, particularly given the lack of the characteristic glycine-arginine-proline (GRP) AT-hook tripeptide (19). Nevertheless, the TgAP2XI-5 AP2 domain itself was highly conserved between T. gondii and either N. caninum (100% identity), P. falciparum (88.5% identity), or P. berghei (86.5% identity) (Fig.…”