Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The yeast transcriptional coactivator GCN5 (yGCN5), a histone acetyltransferase (HAT), is part of large multimeric complexes that are required for chromatin remodeling and transcriptional activation. Like other eukaryotes, the malaria parasite DNA is organized into nucleosomes and the genome encodes components of chromatin-remodeling complexes. Here we show that GCN5 is conserved in Plasmodium species and that the most homologous regions are within the HAT domain and the bromodomain. The Plasmodium falciparum GCN5 homologue (PfGCN5) is spliced with three introns, encoding a protein of 1,464 residues. Mapping of the ends of the PfGCN5 transcript suggests that the mRNA is 5.2 to 5.4 kb, consistent with the result from Northern analysis. Using free core histones, we determined that recombinant PfGCN5 proteins have conserved HAT activity with a substrate preference for histone H3. Using substrate-specific antibodies, we determined that both Lys-8 and -14 of H3 were acetylated by the recombinant PfGCN5. In eukaryotes, GCN5 homologues interact with yeast ADA2 homologues and form large multiprotein HAT complexes. We have identified an ADA2 homologue in P. falciparum, PfADA2. Yeast two-hybrid and in vitro binding assays verified the interactions between PfGCN5 and PfADA2, suggesting that they may be associated with each other in vivo. The conserved function of the HAT domain in PfGCN5 was further illustrated with yeast complementation experiments, which showed that the PfGCN5 region corresponding to the full-length yGCN5 could partially complement the yGCN5 deletion mutation. Furthermore, a chimera comprising the PfGCN5 HAT domain fused to the remainder of yeast GCN5 (yGCN5) fully rescued the yGCN5 deletion mutant. These data demonstrate that PfGCN5 is an authentic GCN5 family member and may exist in chromatin-remodeling complexes to regulate gene expression in P. falciparum.
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PMID:Plasmodium falciparum histone acetyltransferase, a yeast GCN5 homologue involved in chromatin remodeling. 1507 57

The transcriptional coactivator ADA2 is an evolutionarily conserved component of histone acetyltransferase (HAT) complexes involved in chromatin remodeling and transcriptional regulation in eukaryotes. The Plasmodium falciparum homologue, PfADA2, has a 7737 bp open reading frame, encoding a protein of 2578 amino acids with an ADA2-like domain located near the C-terminus. The annotated PfADA2 in the parasite genome is Pf10_143, located on chromosome 10. Sequence analysis demonstrated the presence of an ADA2 homologue in each Plasmodium species selected for genome sequencing. Mapping of the 5' transcriptional initiation sites suggested that PfADA2 transcription was initiated from multiple sites. Northern analysis detected a major transcript of approximately 8.5 kb in erythrocytic stage parasites. An antiserum raised against the internal ADA2-like domain detected multiple proteins from mixed blood stages, suggesting that PfADA2 may be proteolytically processed. In comparison, affinity-purified anti-GCN5 antibodies reacted with a major protein of approximately 200 kDa and immunoprecipitated proteins from the parasite lysate with HAT activity similar to that of the recombinant GCN5. Moreover, this GCN5-like HAT activity could also be precipitated with anti-PfADA2 antibodies, indicating that PfADA2 is associated with PfGCN5 in vivo. To illustrate whether PfADA2 could functionally replace the yADA2, complementation experiments were performed. However, the ADA2-like domain of PfADA2 failed to rescue the yeast ada2(-) mutant, probably due to significant divergence between the two genes. Taken together, these results indicate the presence of PfADA2-PfGCN5 complex(es) in the malaria parasite, which may have conserved functions in chromatin remodeling and gene regulation.
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PMID:PfADA2, a Plasmodium falciparum homologue of the transcriptional coactivator ADA2 and its in vivo association with the histone acetyltransferase PfGCN5. 1524 36

Epigenetic regulatory mechanisms are central to the development and survival of all eukaryotic organisms. These mechanisms critically depend on the marking of chromatin domains with distinctive histone tail modifications (PTMs) and their recognition by effector protein complexes. Here we used quantitative proteomic approaches to unveil interactions between PTMs and associated reader protein complexes of Plasmodium falciparum, a unicellular parasite causing malaria. Histone peptide pull-downs with the most prominent and/or parasite-specific PTMs revealed the binding preference for 14 putative and novel reader proteins. Amongst others, they highlighted the acetylation-level-dependent recruitment of the BDP1/BDP2 complex and identified an PhD-finger protein (PHD 1, PF3D7_1008100) that could mediate a cross-talk between H3K4me2/3 and H3K9ac marks. Tagging and interaction proteomics of 12 identified proteins unveiled the composition of 5 major epigenetic complexes, including the elusive TBP-associated-factor complex as well as two distinct GCN5/ADA2 complexes. Furthermore, it has highlighted a remarkable degree of interaction between these five (sub)complexes. Collectively, this study provides an extensive inventory of PTM-reader interactions and composition of epigenetic complexes. It will not only fuel further explorations of gene regulation amongst ancient eukaryotes, but also provides a stepping stone for exploration of PTM-reader interactions for antimalarial drug development.
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PMID:Epigenetic reader complexes of the human malaria parasite, Plasmodium falciparum. 3172 27