The BRPF1 bromodomain is a molecular reader of di-acetyllysine

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dc.contributor.authorObi, Juliet O.
dc.contributor.authorLubula, Mulu Y.
dc.contributor.authorCornilescu, Gabriel
dc.contributor.authorHenrickson, Amy
dc.contributor.authorMcGuire, Kara
dc.contributor.authorEvans, Chiara M.
dc.contributor.authorPhillips, Margaret
dc.contributor.authorBoyson, Samuel P.
dc.contributor.authorDemeler, Borries
dc.contributor.authorMarkley, John L.
dc.contributor.authorGlass, Karen C.
dc.date.accessioned2021-06-24T22:44:55Z
dc.date.available2021-06-24T22:44:55Z
dc.date.issued2020
dc.descriptionOpen access article. Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) appliesen_US
dc.description.abstractBromodomain-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.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationObi, 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.2020.05.001en_US
dc.identifier.urihttps://hdl.handle.net/10133/5919
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionAlbany College of Pharmacy and Health Sciencesen_US
dc.publisher.institutionUniversity of Wisconsin-Madisonen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1016/j.crstbi.2020.05.001en_US
dc.subjectBromodomainen_US
dc.subjectDi-acetyllysineen_US
dc.subjectEpigeneticsen_US
dc.subjectHistoneen_US
dc.subjectPost-translational modificationsen_US
dc.titleThe BRPF1 bromodomain is a molecular reader of di-acetyllysineen_US
dc.typeArticleen_US
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