Structural and Functional Dissection of the PfBDP1 Ankyrin Repeat Domain as a Reader of Acetylated Histones
Petersen, James
Petersen, James
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Abstract
Histone acetylation is a key epigenetic modification that promotes transcription by weakening histone-DNA interactions and increasing chromatin accessibility. Recognition of acetylated lysine residues has classically been attributed to bromodomains, which are widely regarded as the canonical acetyllysine reader domains. Here, we identify an ankyrin repeat domain (ARD) within Plasmodium falciparum bromodomain protein 1 (PfBDP1) as a non-canonical reader of acetylated histone ligands. Our preliminary data show that the PfBDP1-ARD binds acetylated histone H4 peptides with higher affinity than the PfBDP1 bromodomain. Sequence analysis indicates that the PfBDP1-ARD contains six ankyrin repeats connected by loop regions that may mediate ligand recognition. We hypothesize that these loops form multiple binding pockets that enable coordination of hyper-acetylated histone H4 ligands. To investigate this mechanism, we will generate a structural model of the PfBDP1-ARD in complex with tetra-acetylated histone H4 using AlphaFold to identify candidate hydrogen-bonding and hydrophobic interactions involved in ligand binding. We will then use structure-guided mutagenesis and isothermal titration calorimetry to define residues that weaken or enhance PfBDP1-ARD binding to acetylated histone ligands. These studies will establish the molecular basis by which PfBDP1-ARD selects tri- and tetra-acetylated histone H4 substrates. Collectively, this work expands the current model of acetyllysine recognition beyond bromodomains and identifies an ankyrin repeat domain as a previously unrecognized histone acetylation reader. Because ankyrin repeat domains are highly conserved across eukaryotes, these findings may have broader implications for chromatin regulation and may inform the study of epigenetic mechanisms relevant to cancer and other diseases driven by dysregulated gene expression.
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Date
1/1/2026
Student Status
Senior (Graduating in 2026)
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Poster
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B.S. in neuroscience with pharmacology minor (Expected May 2026) and M.S. in pharmacology (expected May 2027)
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College of Arts and Sciences
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Life Science