Bromodomain: an acetyl‐lysine binding domain

Abstract

Bromodomains, an extensive family of evolutionarily conserved protein modules originally found in proteins associated with chromatin and in nearly all nuclear histone acetyltransferases, have been recently discovered to function as acetyl-lysine binding domains. More recent structural studies of bromodomain/peptide ligand complexes have enriched our understanding of differences in ligand selectivity of bromodomains. These new findings demonstrate that bromodomain/acetyl-lysine recognition can serve as a pivotal mechanism for regulating protein^protein interactions in numerous cellular processes including chromatin remodeling and transcriptional activation, and reinforce the concept that functional diversity of a conserved protein modular structure is achieved by evolutionary changes of amino acid sequences in the ligand binding site. ß

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…In the context of chromatin, histones undergo acetylation to yield a more relaxed chromatin conformation resulting from hydrophobicity, a net change in the overall charge, and reduced electrostatic interactions. Acetylated histones recruit bromodomain-containing proteins, which are primarily transcription factors and cofactors, further enhancing gene expression [20]. HATs are highly conserved from yeasts to humans.…”

“…Thus, it seems essential to envisage direct stimulation of the HAT function, as a new therapeutic tool in neurodegenerative diseases; by directly targeting the remaining HAT(s), one could re-activate the deficient enzymatic function, as well as all the other related functions that are not typically considered using an HDACi strategy. HATs are recruited at promoter loci through, in part, lysine acetylation recognition of conserved bromodomains [20]; together with the proper bound coactivator complexes, HATs acetylate nucleosomes at specific promoter sites (see 4, 5/ in Fig. 3).…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…This generates a tight chromatin structure, refractory to transcription. Moreover, deacetylation reduces the affinity of bromodomain-containing coactivators (Zeng and Zhou, 2002). In this general way, the N-CoR/SMRT complex mediates repression of unliganded nuclear receptors, such as TR, RAR, RXR, PPAR and orphan nuclear receptors, such as Rev-Erb, COUP-TFs, and DAX1 (Shibata et al, 1997;Zamir et al, 1997;Crawford et al, 1998;Jepsen and Rosenfeld, 2002;Yin and Lazar, 2005).…”

Mechanisms of ATP dependent chromatin remodeling

“…The ATPase domain consists of seven subdomains that structurally forms two lobes referred to as the DEXD and helicase motifs that form a cleft to which DNA binds based on X-ray crystal structure from the related Rad54 ATPase domain [41,42]. In addition the Swi2/Snf2 protein contains at its Cterminus a bromo domain which has been shown to recognize specific acetylated lysines in histone tails [43][44][45][46][47][48][49][50]. The Swi1 contains an ARID domain (an AT-rich interaction domain) that is found in its orthologs OSA in Drosophila and BAF250 in mammals.…”