<i>Plasmodium falciparum</i> Bromodomain Protein 1 (PfBDP1): A master regulator of red blood cell invasion genes
Bibliographic record
Abstract
Plasmodium falciparum is a unicellular protozoan parasite that is commonly known to cause malaria in humans. The symptoms of malaria associated with repeated rounds of parasite replication, egress, and invasion into the red blood cells. During the red blood cell stage of malaria infection, PfBDP1 is shown to bind at the transcriptional start sites of invasion-related genes and regulates their expression. A recent spike in malaria infections may be attributed to drug-resistance in P. falciparum, thus we need a better understanding of the parasite's life cycle to produce more effective antimalarial drugs. The P. falciparum genome encodes for ten bromodomain-containing proteins. Previously, the bromodomain of PfBDP1 was shown to preferentially bind acetylated lysine marks on histones, effectively tethering the PfBDP1 transcriptional activator complex to modified nucleosomes within specific chromatin regions. However, the molecular mechanisms driving chromatin binding and recognition by PfBDP1 are not well understood. PfBDP1 contains a unique combination of six ankyrin repeats (ANK) domain followed by a bromodomain (BRD). Bromodomains are evolutionary conserved protein-protein interaction modules (110 amino acids long) that recognize acetylated lysine (Kac) on histones and other proteins. We hypothesized that the bromodomain would modulate the interaction of PfBDP1 with a subset of acetylated histone modifications. We used a structure-function approach including X-ray crystallography, Nuclear Magnetic Resonance (NMR), Small Angle X-ray Scattering (SAXS), analytical ultracentrifugation, and Isothermal Titration Calorimetry (ITC) to characterize the interaction of PfBDP1 with chromatin ligands. The crystal structure of PfBDP1-BRD at 2.0 Å shows that it has a conserved bromodomain fold, and an acetylated lysine binding pocket comprised of four alpha helices. As previously reported, PfBDP1 has been shown to interact with acetylated histone H3, but our in vitro binding experiments revealed that PfBDP1-BRD preferentially binds to tetra-acetylated histone H4. Our data indicate that PfBDP1 has a unique histone ligand binding mechanism that might be leveraged for the design novel therapeutic treatments, and suggest that PfBDP1 may have additional, yet unidentified roles in the P. falciparum life cycle. Plasmodium falciparum is a unicellular protozoan parasite that is commonly known to cause malaria in humans. The symptoms of malaria associated with repeated rounds of parasite replication, egress, and invasion into the red blood cells. During the red blood cell stage of malaria infection, PfBDP1 is shown to bind at the transcriptional start sites of invasion-related genes and regulates their expression. A recent spike in malaria infections may be attributed to drug-resistance in P. falciparum, thus we need a better understanding of the parasite's life cycle to produce more effective antimalarial drugs. The P. falciparum genome encodes for ten bromodomain-containing proteins. Previously, the bromodomain of PfBDP1 was shown to preferentially bind acetylated lysine marks on histones, effectively tethering the PfBDP1 transcriptional activator complex to modified nucleosomes within specific chromatin regions. However, the molecular mechanisms driving chromatin binding and recognition by PfBDP1 are not well understood. PfBDP1 contains a unique combination of six ankyrin repeats (ANK) domain followed by a bromodomain (BRD). Bromodomains are evolutionary conserved protein-protein interaction modules (110 amino acids long) that recognize acetylated lysine (Kac) on histones and other proteins. We hypothesized that the bromodomain would modulate the interaction of PfBDP1 with a subset of acetylated histone modifications. We used a structure-function approach including X-ray crystallography, Nuclear Magnetic Resonance (NMR), Small Angle X-ray Scattering (SAXS), analytical ultracentrifugation, and Isothermal Titration Calorimetry (ITC) to characterize the interaction of PfBDP1 with chromatin ligands. The crystal structure of PfBDP1-BRD at 2.0 Å shows that it has a conserved bromodomain fold, and an acetylated lysine binding pocket comprised of four alpha helices. As previously reported, PfBDP1 has been shown to interact with acetylated histone H3, but our in vitro binding experiments revealed that PfBDP1-BRD preferentially binds to tetra-acetylated histone H4. Our data indicate that PfBDP1 has a unique histone ligand binding mechanism that might be leveraged for the design novel therapeutic treatments, and suggest that PfBDP1 may have additional, yet unidentified roles in the P. falciparum life cycle.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".