Molecular basis of histone acetyllysine recognition by the BRPF1 bromodomain (537.1)

Abstract

Covalent modifications on histone tails play a key role in determining the outcome of many nuclear processes including transcription, DNA repair, recombination, and replication. In humans, translocation of the monocytic leukemia zinc finger (MOZ) histone acetyltransferase (HAT) complex has been linked to a subtype of acute myeloid leukemia (AML). MOZ forms tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1‐associated factor 6 ortholog), and the bromodomain‐PHD finger protein. BRPF proteins have been shown to bridge the association of MOZ with ING5 and EAF6. Deletion mapping studies have also revealed that the acetyltransferase domain of MOZ is sufficient for the interaction with BRPF1. BRPF proteins therefore play a key role in assembling and activating MOZ acetyltransferase complexes. BRPF1 contains a unique combination of domains typically found in chromatin‐associated factors, including PHD (plant homeodomain) fingers, a bromodomain and a PWWP (Pro‐Trp‐Trp‐Pro) domain. The bromodomain and PWWP domain of BRPF1 help recruit MOZ to distinct sites of active chromatin. Bromodomains are highly conserved motifs generally known to acetylated lysines on the histone tail, but the ligands recognized by BRPF1 bromodomain are currently unknown. In this study we identified the N‐terminal histone tail ligands for the BRPF1 bromodomain, characterized the protein‐ligand binding affinities and determined the functional importance of these interactions. We also used extensive molecular dynamics simulations to generate structural models of bromodomain‐histone ligand complexes, to analyze H‐bonding and other interactions, and to calculate the binding free energies. Our results outline the molecular mechanism driving binding specificity of the BRPF1 bromodomain for discrete acetyllysine residues on the N‐terminal histone tails. A better understanding of this process will be important for the development of drugs to treat acute myeloid leukemia and other cancers.Grant Funding Source: NIH