5gh9
Crystal structure of CBP Bromodomain with H3K56ac peptide
Structural highlights
DiseaseCBP_HUMAN Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:180849. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.[1] [2] [3] [4] FunctionCBP_HUMAN Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.[5] [6] [7] [8] Publication Abstract from PubMedThe acetylation of lysine 56 of histone H3 (H3K56ac) enhances the binding affinity of histone chaperones to H3-H4 dimers. CREB binding protein (CBP) possesses a bromodomain that recognizes H3K56 acetylation. CBP also possesses a histone acetyltransferase (HAT) domain, which has been shown to promote H3K56 acetylation of free histones to facilitate delivery of replication-dependent chaperones to acetylated histones for chromatin assembly. However, the mechanism by which the CBP bromodomain recognizes H3K56ac, and thecontext in which such recognition occurs remains elusive. Here, we solved the crystal structure of the CBP bromodomain in complex with an H3K56ac peptide. Our data demonstrate that the CBP bromodomain recognizes H3K56ac with high affinity. Structural and affinity analyses reveal that the CBPbromodomain prefers an aromatic residue at the -2 position and an arginine at the -4 position from the acetyl-lysine, and that the CBP bromodomain selectively recognizes an extended conformation of the H3 alphaN helix that contains H3K56ac. We also demonstrate that the CBP bromodomain binds to H3K56ac in a recombinant H3-H4 dimer but not in a mono-nucleosome. Our results suggest that the CBP bromodomain selectively recognizes an extended conformation of the K56-acetylated H3 alphaN region within an H3-H4 dimer, which is expected to facilitate the HAT activity of CBP for subsequent H3K56 acetylation of free histones. This article is protected by copyright. All rights reserved. Structural insight into CBP bromodomain-mediated recognition of acetylated histone H3K56ac.,Xu L, Cheng A, Huang M, Zhang J, Jiang Y, Wang C, Li F, Bao H, Gao J, Wang N, Liu J, Wu J, Wong CCL, Ruan K FEBS J. 2017 Aug 16. doi: 10.1111/febs.14198. PMID:28815970[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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