From Proteopedia

BRPF1 Bromodomain

General description

Schematic representation of the MOZ/MORF histone acetyltransferase (HAT) complex with different subunits shown in different colors. The Brpf1 subunit contains a unique combination of domains including two PHD fingers, a bromodomain and a PWWP domain.An sequence alignment of the BRPF1 bromodomain with other bromodomains in the family 5 of bromodomains was created with Expresso (using stuctural information), and is shown in the lower portion of the image. Location of structural elements are at the top of the alignment above the BRPF1 bromodomain, which is used as a reference for amino acid numbering.

Covalent modifications of histone tails play a key role in determining the outcome of many nuclear processes including transcription, DNA repair, recombination, and replication. It is central to cell homeostasis, as alterations in chromatin structure contribute to the development of cancer and other human diseases. In human, translocation of the MOZ/MORF histone acetyltransferase (HAT) complex has been linked to a subtype of acute myeloid leukemia (AML)^[1]. MOZ/MORF forms tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. BRPF proteins have been shown to bridge the association of MOZ/MORF with ING5 and EAF6. Deletion mapping studies have also revealed that the acetyltransferase domain of MOZ/MORF is sufficient for BRPF1 interaction. BRPF proteins therefore play a key role in assembling and activating MOZ/MORF acetyltransferase complexes. Brpf1 contains a unique combination of domains typically found in chromatin-associated factors, including PHD fingers, a bromodomain and a PWWP domain. These domains help recruit MOZ/MORF to distinct sites of active chromatin. Bromodomains are highly conserved motifs generally known to bind (read) histones acetylated at their lysine residues. Despite their highly conserved αZ, αA, αB, and αC regions, variations in the αAZ and αBC regions of bromodomains help them distinguish between different acetylated lysine residues. Although it may be expected that, like all known bromodomains, the BRPF1 bromodomain can recognize/read acetylated lysine, the exact modification(s) that this bromodomain can recognize are still subject to elucidation.

Structural description

Like all known bromodomains, the BRPF1 bromodamain adopts a conserved structural fold of a left-handed bundle of four helices (αZ, αA, αB, and αC ) with the inter-helical ZA and BC loops having variable length and sequence. The latter loops constitute a hydrophobic pocket serving to stabilize the structure as well as to interact with the acetyl-lysine.

Structural insigts into function

Based on the observed high sequence similarity with well characterized bromodomains, the BRPF1 bromodomain may be expected to recognize/read acetylated lysine. However additional studies are needed to identify the exact modifications that the BRPF1 bromodomain may recognize/read.

References

1. ↑ Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Cote J, Yang XJ. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol. 2008 Nov;28(22):6828-43. doi: 10.1128/MCB.01297-08. Epub 2008 Sep , 15. PMID:18794358 doi:10.1128/MCB.01297-08