Coordination of di-acetylated histone ligands by the ATAD2 bromodomain

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dc.contributor.authorEvans, Chiara M.
dc.contributor.authorPhillips, Margaret
dc.contributor.authorMalone, Kiera L.
dc.contributor.authorTonelli, Marco
dc.contributor.authorCornilescu, Gabriel
dc.contributor.authorCornilescu, Claudia
dc.contributor.authorHolton, Simon J.
dc.contributor.authorGorjánácz, Mátyás
dc.contributor.authorWang, Liping
dc.contributor.authorCarlson, Samuel
dc.contributor.authorGay, Jamie C.
dc.contributor.authorNix, Jay C.
dc.contributor.authorDemeler, Borries
dc.contributor.authorMarkley, John L.
dc.contributor.authorGlass, Karen C.
dc.date.accessioned2022-08-26T20:53:57Z
dc.date.available2022-08-26T20:53:57Z
dc.date.issued2021
dc.descriptionOpen access article. Creative Commons Attribution 4.0 International license (CC BY 4.0) appliesen_US
dc.description.abstractThe ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four -helices. ATAD2 functions as a coactivator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the “RVF” shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationEvans, C. M., Phillips, M., Malone, K. L., Tonelli, M., Cornilescu, G., Cornilescu, C., Holton, S. J., Gorjánácz, M., Wang, L., Carlson, S., Gay, J. C., Nix, J. C., Demeler, B., Markley, J. L., & Glass, K. C. (2021). Coordination of di-acetylated histone ligands by the ATAD2 bromodomain. International Journal of Molecular Sciences, 22(17), Article E9128. https://doi.org/10.3390/ijms22179128en_US
dc.identifier.urihttps://hdl.handle.net/10133/6326
dc.language.isoen_USen_US
dc.publisherMDPIen_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 Vermonten_US
dc.publisher.institutionUniversity of Wisconsin-Madisonen_US
dc.publisher.institutionBayer AGen_US
dc.publisher.institutionUniversity of Texas Health San Antonioen_US
dc.publisher.institutionMolecular Biology Consortiumen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.3390/ijms22179128en_US
dc.subjectATAD2 bromodomainen_US
dc.subjectAcetylated histonesen_US
dc.subjectPost-translational modificationsen_US
dc.subjectIsothermal titration calorimetryen_US
dc.subjectAnalytical ultracentrifugationen_US
dc.subjectChromatin reader domainen_US
dc.subject.lcshPost-translational modification
dc.subject.lcshX-ray crystallography
dc.subject.lcshNuclear magnetic resonance
dc.subject.lcshUltracentrifugation
dc.subject.lcshCancer
dc.subject.lcshEpigenetics
dc.titleCoordination of di-acetylated histone ligands by the ATAD2 bromodomainen_US
dc.typeArticleen_US
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