The BRPF1 bromodomain is a molecular reader of di-acetyllysine
Date
2020
Authors
Obi, Juliet O.
Lubula, Mulu Y.
Cornilescu, Gabriel
Henrickson, Amy
McGuire, Kara
Evans, Chiara M.
Phillips, Margaret
Boyson, Samuel P.
Demeler, Borries
Markley, John L.
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Bromodomain-containing proteins are often part of chromatin-modifying complexes, and their activity can lead toaltered expression of genes that drive cancer, inflammation and neurological disorders in humans. Bromodomain-PHDfinger protein 1 (BRPF1) is part of the MOZ (monocytic leukemic zinc-finger protein) HAT (histone ace-tyltransferase) complex, which is associated with chromosomal translocations known to contribute to thedevelopment of acute myeloid leukemia (AML). BRPF1 contains a unique combination of chromatin reader do-mains including two plant homeodomain (PHD)fingers separated by a zinc knuckle (PZP domain), a bromodo-main, and a proline-tryptophan-tryptophan-proline (PWWP) domain. BRPF1 is known to recruit the MOZ HATcomplex to chromatin by recognizing acetylated lysine residues on the N-terminal histone tail region through itsbromodomain. However, histone proteins can contain several acetylation modifications on their N-terminus, andit is unknown how additional marks influence bromodomain recruitment to chromatin. Here, we identify theBRPF1 bromodomain as a selective reader of di-acetyllysine modifications on histone H4. We used ITC assays tocharacterize the binding of di-acetylated histone ligands to the BRPF1 bromodomain and found that the domainbinds preferentially to histone peptides H4K5acK8ac and H4K5acK12ac. Analytical ultracentrifugation (AUC)experiments revealed that the monomeric state of the BRPF1 bromodomain coordinates di-acetylated histoneligands. NMR chemical shift perturbation studies, along with binding and mutational analyses, revealed non-canonical regions of the bromodomain-binding pocket that are important for histone tail recognition. Together,ourfindings provide critical information on how the combinatorial action of post-translational modifications canmodulate BRPF1 bromodomain binding and specificity.
Description
Open access article. Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) applies
Keywords
Bromodomain , Di-acetyllysine , Epigenetics , Histone , Post-translational modifications
Citation
Obi, J. O., Lubula, M. Y., Cornilescu, G., Henrickson, A., McGuire, K., Evans, C. M., Phillips, M., Boyson, S. P., Demeler, B., Markley, J. L., & Glass, K. C. (2020). The BRPF1 bromodomain is a molecular reader of di-acetyllysine. Current Research in Structural Biology, 2, 104-115. https://doi.org/10.1016/j.crstbi.2020.05.001