Structural insights into acetylated histone ligand recognition by the $\mathrm{BDP1}$ bromodomain of Plasmodium falciparum

Singh, Ajit Kumar; Phillips, Margaret; Alkrimi, Saleh; Tonelli, Marco; Boyson, Samuel P.; Malone, Kiera L.; Nix, Jay C.; Glass, Karen C.

doi:10.1016/j.ijbiomac.2022.10.247

Structural insights into acetylated histone ligand recognition by the $$\mathrm{BDP1}$$ bromodomain of Plasmodium falciparum

Journal Article · Mon Oct 31 00:00:00 EDT 2022 · International Journal of Biological Macromolecules

DOI:https://doi.org/10.1016/j.ijbiomac.2022.10.247· OSTI ID:2278647

Singh, Ajit Kumar ^[1]; Phillips, Margaret ^[1]; Alkrimi, Saleh ^[2]; Tonelli, Marco ^[3]; Boyson, Samuel P. ^[2]; Malone, Kiera L. ^[1]; Nix, Jay C. ^[4]; Glass, Karen C. ^[5]

University of Vermont, Burlington, VT (United States)
Albany College of Pharmacy and Health Sciences, Colchester, VT (United States)
University of Wisconsin, Madison, WI (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
University of Vermont, Burlington, VT (United States); Albany College of Pharmacy and Health Sciences, Colchester, VT (United States)

Plasmodium falciparum requires a two-host system, moving between Anopheles mosquito and humans, to complete its life cycle. To overcome such dynamic growth conditions its histones undergo various post-translational modifications to regulate gene expression. The P. falciparum Bromodomain Protein 1 (PfBDP1) has been shown to interact with acetylated lysine modifications on histone H3 to regulate the expression of invasion-related genes. Here, we investigated the ability of the PfBDP1 bromodomain to interact with acetyllsyine modifications on additional core and variant histones. A crystal structure of the PfBDP1 bromodomain (PfBDP1-BRD) reveals it contains the conserved bromodomain fold, but our comparative analysis between the PfBDP1-BRD and human bromodomain families indicates it has a unique binding mechanism. Solution NMR spectroscopy and ITC binding assays carried out with acetylated histone ligands demonstrate that it preferentially recognizes tetra-acetylated histone H4, and we detected weaker interactions with multi-acetylated H2A.Z in addition to the previously reported interactions with acetylated histone H3. Our findings indicate PfBDP1 may play additional roles in the P. falciparum life cycle, and the distinctive features of its bromodomain binding pocket could be leveraged for the development of new therapeutic agents to help overcome the continuously evolving resistance of P. falciparum against currently available drugs.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2278647

Journal Information:: International Journal of Biological Macromolecules, Journal Name: International Journal of Biological Macromolecules Journal Issue: Pt A Vol. 223; ISSN 0141-8130

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (45)

NMRbot: Python scripts enable high-throughput data collection on current Bruker BioSpin NMR spectrometers Clos, Lawrence J.; Jofre, M. Fransisca; Ellinger, James J. Metabolomics, Vol. 9, Issue 3 https://doi.org/10.1007/s11306-012-0490-9	journal	January 2013
Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases Padmanabhan, Balasundaram; Mathur, Shruti; Manjula, Ramu Journal of Biosciences, Vol. 41, Issue 2 https://doi.org/10.1007/s12038-016-9600-6	journal	April 2016
Indirect effects of the COVID-19 pandemic on malaria intervention coverage, morbidity, and mortality in Africa: a geospatial modelling analysis Weiss, Daniel J.; Bertozzi-Villa, Amelia; Rumisha, Susan F. The Lancet Infectious Diseases, Vol. 21, Issue 1 https://doi.org/10.1016/S1473-3099(20)30700-3	journal	January 2021
Malaria: Could its unusual epigenome be the weak spot? Salcedo-Amaya, Adriana M.; Hoeijmakers, Wieteke A. M.; Bártfai, Richard The International Journal of Biochemistry & Cell Biology, Vol. 42, Issue 6 https://doi.org/10.1016/j.biocel.2010.03.010	journal	June 2010
Chromatin Modifications and Their Function Kouzarides, Tony Cell, Vol. 128, Issue 4 https://doi.org/10.1016/j.cell.2007.02.005	journal	February 2007
Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family Filippakopoulos, Panagis; Picaud, Sarah; Mangos, Maria Cell, Vol. 149, Issue 1 https://doi.org/10.1016/j.cell.2012.02.013	journal	March 2012
A Plasmodium Falciparum Bromodomain Protein Regulates Invasion Gene Expression Josling, Gabrielle A.; Petter, Michaela; Oehring, Sophie C. Cell Host & Microbe, Vol. 17, Issue 6 https://doi.org/10.1016/j.chom.2015.05.009	journal	June 2015
Chromatin Accessibility-Based Characterization of the Gene Regulatory Network Underlying Plasmodium falciparum Blood-Stage Development Toenhake, Christa Geeke; Fraschka, Sabine Anne-Kristin; Vijayabaskar, Mahalingam Shanmugiah Cell Host & Microbe, Vol. 23, Issue 4 https://doi.org/10.1016/j.chom.2018.03.007	journal	April 2018
The bromodomain interaction module Filippakopoulos, Panagis; Knapp, Stefan FEBS Letters, Vol. 586, Issue 17 https://doi.org/10.1016/j.febslet.2012.04.045	journal	May 2012
The malaria parasite Plasmodium falciparum histones: Organization, expression, and acetylation Miao, Jun; Fan, Qi; Cui, Long Gene, Vol. 369 https://doi.org/10.1016/j.gene.2005.10.022	journal	March 2006
PHD fingers in human diseases: Disorders arising from misinterpreting epigenetic marks Baker, Lindsey A.; Allis, C. David; Wang, Gang G. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 647, Issue 1-2 https://doi.org/10.1016/j.mrfmmm.2008.07.004	journal	December 2008
Dynamic Chromatin Structure and Epigenetics Control the Fate of Malaria Parasites Hollin, Thomas; Gupta, Mohit; Lenz, Todd Trends in Genetics, Vol. 37, Issue 1 https://doi.org/10.1016/j.tig.2020.09.003	journal	January 2021
Place your BETs: the therapeutic potential of bromodomains Prinjha, R. K.; Witherington, J.; Lee, K. Trends in Pharmacological Sciences, Vol. 33, Issue 3 https://doi.org/10.1016/j.tips.2011.12.002	journal	March 2012
Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite Saraf, Anita; Cervantes, Serena; Bunnik, Evelien M. Journal of Proteome Research, Vol. 15, Issue 8 https://doi.org/10.1021/acs.jproteome.6b00366	journal	June 2016
The Bromodomain: A New Target in Emerging Epigenetic Medicine Smith, Steven G.; Zhou, Ming-Ming ACS Chemical Biology, Vol. 11, Issue 3 https://doi.org/10.1021/acschembio.5b00831	journal	December 2015
Expanding Bromodomain Targeting into Neglected Parasitic Diseases Tallant, Cynthia; Bamborough, Paul; Chung, Chun-wa ACS Infectious Diseases, Vol. 7, Issue 11 https://doi.org/10.1021/acsinfecdis.1c00387	journal	October 2021
Nucleosome Structure and Function McGinty, Robert K.; Tan, Song Chemical Reviews, Vol. 115, Issue 6 https://doi.org/10.1021/cr500373h	journal	October 2014
Global Histone Analysis by Mass Spectrometry Reveals a High Content of Acetylated Lysine Residues in the Malaria Parasite Plasmodium falciparum Trelle, Morten B.; Salcedo-Amaya, Adriana M.; Cohen, Adrian M. Journal of Proteome Research, Vol. 8, Issue 7 https://doi.org/10.1021/pr9000898	journal	June 2009
Crystal structure of the nucleosome core particle at 2.8 Å resolution Luger, Karolin; Mäder, Armin W.; Richmond, Robin K. Nature, Vol. 389, Issue 6648 https://doi.org/10.1038/38444	journal	September 1997
The language of covalent histone modifications Strahl, Brian D.; Allis, C. David Nature, Vol. 403, Issue 6765 https://doi.org/10.1038/47412	journal	January 2000
Regulation of chromatin by histone modifications Bannister, Andrew J.; Kouzarides, Tony Cell Research, Vol. 21, Issue 3 https://doi.org/10.1038/cr.2011.22	journal	February 2011
Cooperative binding of two acetylation marks on a histone tail by a single bromodomain Morinière, Jeanne; Rousseaux, Sophie; Steuerwald, Ulrich Nature, Vol. 461, Issue 7264 https://doi.org/10.1038/nature08397	journal	October 2009
Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites Coetzee, Nanika; von Grüning, Hilde; Opperman, Daniel Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-59298-4	journal	February 2020
Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition Amodeo, Amanda A.; Jukam, David; Straight, Aaron F. Proceedings of the National Academy of Sciences, Vol. 112, Issue 10 https://doi.org/10.1073/pnas.1413990112	journal	February 2015
Developments in drug design strategies for bromodomain protein inhibitors to target Plasmodium falciparum parasites Nguyen, Hanh H. T.; Yeoh, Lee M.; Chisholm, Scott A. Expert Opinion on Drug Discovery, Vol. 15, Issue 4 https://doi.org/10.1080/17460441.2020.1704251	journal	December 2019
NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy Lee, Woonghee; Tonelli, Marco; Markley, John L. Bioinformatics, Vol. 31, Issue 8 https://doi.org/10.1093/bioinformatics/btu830	journal	December 2014
A model for particulate structure in chromatin Van Hoide, K. E.; Sahasrabuddhe, C. G.; Shaw, Barbara Ramsay Nucleic Acids Research, Vol. 1, Issue 11 https://doi.org/10.1093/nar/1.11.1579	journal	January 1974
The Histone Database Sullivan, S. Nucleic Acids Research, Vol. 30, Issue 1 https://doi.org/10.1093/nar/30.1.341	journal	January 2002
Epigenetic reader complexes of the human malaria parasite, Plasmodium falciparum Hoeijmakers, Wieteke Anna Maria; Miao, Jun; Schmidt, Sabine Nucleic Acids Research, Vol. 47, Issue 22 https://doi.org/10.1093/nar/gkz1044	journal	November 2019
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Integration, scaling, space-group assignment and post-refinement Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 133-144 https://doi.org/10.1107/S0907444909047374	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
H2A.Z/H2B.Z double‐variant nucleosomes inhabit the AT‐rich promoter regions of the Plasmodium falciparum genome Hoeijmakers, Wieteke A. M.; Salcedo‐Amaya, Adriana M.; Smits, Arne H. Molecular Microbiology, Vol. 87, Issue 5 https://doi.org/10.1111/mmi.12151	journal	January 2013
Translating the Histone Code Jenuwein, T. Science, Vol. 293, Issue 5532 https://doi.org/10.1126/science.1063127	journal	August 2001
PfGCN5-Mediated Histone H3 Acetylation Plays a Key Role in Gene Expression in Plasmodium falciparum Cui, Long; Miao, Jun; Furuya, Tetsuya Eukaryotic Cell, Vol. 6, Issue 7 https://doi.org/10.1128/EC.00062-07	journal	July 2007
Architectural Epigenetics: Mitotic Retention of Mammalian Transcriptional Regulatory Information Zaidi, Sayyed K.; Young, Daniel W.; Montecino, Martin Molecular and Cellular Biology, Vol. 30, Issue 20 https://doi.org/10.1128/MCB.00646-10	journal	October 2010
Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development Jeffers, Victoria; Yang, Chunlin; Huang, Sherri Microbiology and Molecular Biology Reviews, Vol. 81, Issue 1 https://doi.org/10.1128/MMBR.00047-16	journal	March 2017
Acetylation of Histones and Transcription-Related Factors Sterner, D. E.; Berger, S. L. Microbiology and Molecular Biology Reviews, Vol. 64, Issue 2 https://doi.org/10.1128/MMBR.64.2.435-459.2000	journal	June 2000
Nucleosome Structure(s) and Stability: Variations on a Theme Andrews, Andrew J.; Luger, Karolin Annual Review of Biophysics, Vol. 40, Issue 1 https://doi.org/10.1146/annurev-biophys-042910-155329	journal	June 2011
Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up Praet, Nicolas; Asante, Kwaku Poku; Bozonnat, Marie-Cecile Malaria Journal, Vol. 21, Issue 1 https://doi.org/10.1186/s12936-022-04144-3	journal	April 2022
Willingness to accept malaria vaccine among caregivers of under-5 children in Southwest Ethiopia: a community based cross-sectional study Asmare, Getachew Malaria Journal, Vol. 21, Issue 1 https://doi.org/10.1186/s12936-022-04164-z	journal	May 2022
Histone modifications associated with gene expression and genome accessibility are dynamically enriched at Plasmodium falciparum regulatory sequences Tang, Jingyi; Chisholm, Scott A.; Yeoh, Lee M. Epigenetics & Chromatin, Vol. 13, Issue 1 https://doi.org/10.1186/s13072-020-00365-5	journal	November 2020
The Putative Bromodomain Protein PfBDP7 of the Human Malaria Parasite Plasmodium Falciparum Cooperates With PfBDP1 in the Silencing of Variant Surface Antigen Expression Quinn, Jennifer E.; Jeninga, Myriam D.; Limm, Katharina Frontiers in Cell and Developmental Biology, Vol. 10 https://doi.org/10.3389/fcell.2022.816558	journal	April 2022
Sticking for a Cause: The Falciparum Malaria Parasites Cytoadherence Paradigm Lee, Wenn-Chyau; Russell, Bruce; Rénia, Laurent Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.01444	journal	June 2019
The Role of Bromodomain Proteins in Regulating Gene Expression Josling, Gabrielle A.; Selvarajah, Shamista A.; Petter, Michaela Genes, Vol. 3, Issue 2 https://doi.org/10.3390/genes3020320	journal	May 2012

Similar Records

Solution structure of BRD7 bromodomain and its interaction with acetylated peptides from histone H3 and H4

Journal Article · Fri Jun 29 00:00:00 EDT 2007 · Biochemical and Biophysical Research Communications · OSTI ID:20991407

Structural Insights into Selective Histone H3 Recognition by the Human Polybromo bromodomain 2

Journal Article · Thu Dec 31 23:00:00 EST 2009 · Cell Research · OSTI ID:1020219

Autoregulation of the Rsc4 Tandem Bromodomain by Gcn5 Acetylation

Journal Article · Sun Dec 31 23:00:00 EST 2006 · Molecular Cell · OSTI ID:959939

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
BRD
ITC
NMR
P. falciparum
P. falciparum bromodomain-containing protein 1
PTM
PfBDP1
bromodomain
chromatin reader domains
epigenetics
histones
isothermal titration calorimetry
malaria
nuclear magnetic resonance
plasmodium falciparum
post-translational modifications
x-ray crystallography

Structural insights into acetylated histone ligand recognition by the $$\mathrm{BDP1}$$ bromodomain of Plasmodium falciparum

Citation Formats

References (45)

Similar Records

Related Subjects