User:Saleh Alkrimi/ Sandbox 898

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Introduction

PfBDP1 plays a key role in the coordinate regulation of genes involved in erythrocyte invasion and thus in the proliferation of malaria parasites. PfBDP1 regulates invasion-related gene expression through binding to acetylated histones present in nucleosomes at regulatory sites^[3]. Bromodomains are evolutionarily conserved protein modules that specifically recognize acetylated lysine residues on histone tails of the nucleosome. During red-blood-cell-stage infection of Plasmodium falciparum, the parasite undergoes repeated rounds of replication, egress, and invasion. Erythrocyte invasion involves specific interactions between host cell receptors and parasite ligands and coordinated expression of genes specific to this step of the life cycle. Parasite-specific bromodomain protein, PfBDP1, binds to chromatin at transcriptional start sites of invasion-related genes and directly controls their expression. A parasite-specific bromodomain protein, PfBDP1 is essential in malaria parasites. PfBDP1 binds to chromatin at invasion gene promoters. Depletion of PfBDP1 dysregulates invasion gene expression and disrupts invasion. PfBDP1 as a critical activator of the coordinate expression of genes that encode proteins with an essential role in erythrocyte invasion.

Structure Features

PfBDP1 (PF3D7_1033700), is a 55 kDa protein. The protein sequence is given in Figure below. The bromodomain is contained within residues 333-456 of the entire protein sequence of PfBDP1 which is composed of 488 amino acid residues, and includes all of the twenty common amino acids, and has a total molecular weight of 19773.77

As shown in Figure below, the domain architecture of P. falciparum bromodomain protein 1 (PfBDP1) contains a single C-terminal bromodomain and a number of ankyrin repeats (in the N-terminal portion of the protein, presumably operating in protein-protein interactions); this architecture appears to be unique to apicomplexan parasites.

Bromodomain Histone Ligand Recognition

P. falciparum histones H3 and H4 are extremely rich in euchromatin-associated PTMs and largely devoid of heterochromatin-associated marks, as observed in other unicellular eukaryotes. Mass spectrometry shows that P. falciparum histone H3 is acetylated at lysines 9, 14, 18 and 27, and that on histone H4 lysines 8 and 12 are also acetylated in vivo. Western blots with modification‐specific antibodies confirm acetylation at several other residues as well^[4]. PfBDP1 bromodomain can recognize different acetyllysine histone ligands with varying binding affinities. Currently, it is known that PfBDP1 binds to acetylated histone H3, and it predominantly recognizes H3K9ac and H3K14ac^[5] PfBDP1 was shown to positively regulate transcription of invasion genes

Sequence alignment

Evolutionary Conservation

The P. falciparum genome encodes four evolutionarily conserved, canonical core histones, H2A, H2B, H3, and H4^[6], and four variant histones, H2A.Z, H2Bv, H3.3, and CenH3, all of which have been confirmed by mass spectrometry (MS)^[7]. The linker histone H1 has not been recognized, which partially explains the lack of higher-order compaction of nuclear DNA in P. falciparum. Consistent with required histone deposition during DNA replication, the core histones are highly expressed in late trophozoite and schizont stages^[8], coinciding with DNA synthesis^[9]. H2Bv is lineage-specific and is found in trypanosomes and apicomplexan parasites^[10]. The replacement of canonical histones with histone variants can influence the nucleosome stability and chromatin patterns.

Function

PfBDP1 has been shown to be involved in the regulation of invasion-related genes in asexual stage parasites. Also, it appears to be essential for parasite growth^[11]. conditional knockdown of PfBDP1 resulted in erythrocyte invasion defects and parasite growth inhibition, further confirming the essentiality of this bromodomain protein for the coordinated expression of invasion genes in P. falciparum^[12]. PfBDP1 Interacts with a Second Bromodomain Protein Bromodomain proteins generally function as part of larger complexes, where they act to recruit factors that can influence chromatin structure^[13] PfBDP1, binds to chromatin at transcriptional start sites of invasion-related genes and directly controls their expression. bromodomain protein (PfBDP1), directly exerts positive regulation of invasion genes and is required for normal erythrocyte invasion^[14].

Medical Important

The importance of the bromodomain protein PfBDP1 in regulating parasite growth and the feasibility of bromodomain inhibitors as therapeutics establish PfBDP1 as an exciting potential drug target^[15]. Malaria is a major public health problem in many developing countries, with the malignant tertian parasite Plasmodium falciparum causing the most malaria-associated mortality.

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