Date of Completion
2023
Document Type
Honors College Thesis
Department
Biochemistry
Thesis Type
College of Arts and Science Honors, Honors College
First Advisor
Karen Glass
Second Advisor
Matthew Liptak
Keywords
bromodomain, structural biology, biochemistry, malaria
Abstract
DNA in eukaryotic cells is compressed into chromatin, a tightly wound complex of nucleic acids and protein, and chromatin structure is important in the regulation of gene expression. The nucleosome is the core unit of chromatin, is comprised of a histone octamer wrapped by DNA, and often contains chemical modifications on its histone proteins that signal to turn gene expression on or off. These histone modifications result in altered chromosomal accessibility to RNA polymerase. Bromodomains are evolutionarily conserved readers of a specific type of histone modification when a lysine amino acid is acetylated (Dhalluin, et al., 1999).
The parasite Plasmodium falciparum is the main cause of malaria infections, and undergoes a repeated cycle of replications, egress, and invasion (Kumar, 2019). Plasmodium falciparum bromodomain protein 1 (PfBDP1), binds to chromatin at the transcriptional start site of invasion-related genes and is therefore essential for malarial invasion of red blood cells. (Josling, et al., 2015). Knockdown of PfBDP1 results in down-regulation of invasion related genes and lower levels of parasite invasion, whereas upregulation of PfBDP1 results in higher levels of expression of these same invasion related genes.
Although we know PfBDP1 plays an important role in regulating the invasion process, the molecular interactions driving its activity, the native state of the active protein, and how PfBDP1 is recruited to the chromatin has not been characterized. This thesis aims to characterize the native state of the full-length PfBDP1 protein and determine which acetylated histone ligands are preferred by PfBDP1. Deducing the structural and functional interactions of PfBDP1 with chromatin will open up the possibility for researchers to use PfBDP1 as a drug target for malaria.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Recommended Citation
Vulikh, Mirabella, "Structural and Functional Analysis of Plasmodium flaciparum Bromodomain Protein 1" (2023). UVM Patrick Leahy Honors College Senior Theses. 523.
https://scholarworks.uvm.edu/hcoltheses/523