Abstract
Bromodomains are often found in chromatin‐modifying complexes, whose activity can lead to aberrant expression of genes that drive certain diseases in humans, including cancer, neurological disorders and inflammation. The bromodomain‐PHD finger protein 1 (BRPF1) is a part of the MOZ (monocytic leukemic zinc‐finger protein) HAT (histone acetyltransferase) complex implicated in chromosomal translocations known to contribute to the development of acute myeloid leukemia (AML). BRPF1 contains a unique combination of post‐translational modification (PTM) reader domains, including two plant homeodomain (PHD) fingers, a bromodomain, and a proline‐tryptophan‐tryptophan‐proline (PWWP) domain, through which it is known to modulate the HAT activity of MOZ. We hypothesized that the BRPF1 bromodomain can recognize histone ligands with multiple acetyllysine marks, and that the recognition can be modulated by PTMs adjacent to these marks. We carried out isothermal titration calorimetry (ITC), analytical ultracentrifugation (AU), and site‐directed mutagenesis experiments with the purified BRPF1 bromodomain to investigate its binding affinity to different di‐acetyllysine histone ligands. Our data reveal the BRPF1 bromodomain is able to bind several histone ligands containing di‐acetyllysine, and modifications adjacent to the acetyllysine modifications alter the binding affinity. Notably, our AU data show that the BRPF1 bromodomain binds to mono‐ and di‐acetyllysine ligands as a monomer. Our studies will further elucidate the role of the bromodomain in recruiting BRPF1 to histones, and subsequently assembling and activating the MOZ HAT complex, which has been implicated in acute myeloid leukemia.Support or Funding InformationNational Institutes of Health, National Institute of General Medical Sciences grant number R15GM104865 to KCGThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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