Molecular Basis of Histone Acetyllysine Recognition by the BRPF1 Bromodomain

Abstract

The monocytic leukemic zinc‐finger (MOZ) histone acetyltransferase (HAT) was first identified as a fusion partner with the CREB binding protein (CBP) in a chromosomal translocation found in acute myeloid leukemia (AML). Disruption of MOZ HAT activity leads to leukemogenic transformations and oncogenesis. Bromodomain‐PHD finger protein 1 (BRPF1) is essential for MOZ HAT activity and links the MOZ catalytic subunit to the inhibitor of growth 5 (ING5) and hEaf6 subunits in the complex. BRPF1 also contains multiple epigenetic reader domains including a unique double plant homeodomain (PHD), a bromodomain (BRD) and a PWWP domain. These chromatin reader domains recognize post‐translationally modified histones and are often found in nuclear proteins that control fundamental cellular processes including gene transcription, DNA replication and recombination. Retention of these domains in leukemic fusion proteins is speculated to direct aberrant HAT activity and may be responsible for oncogenic transformations. However, the histone target(s) of the BRPF1 BRD are unknown, and its role in modulating the activity of the MOZ HAT complex is not well understood. A unique combination of peptide array, nuclear magnetic resonance, isothermal titration calorimetry and molecular docking experiments were used to identify the BRPF1 BRD ligands and characterize the molecular determinants driving histone recognition.