Solution Structure of Human Brg1 Bromodomain and Its Specific Binding to Acetylated Histone Tails

详细信息    查看全文

• 作者：Weiqun Shen ; Chao Xu ; Wei Huang ; Jiahai Zhang ; Justin E. Carlson ; Xiaoming Tu ; Jihui Wu ; Yunyu Shi
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：February 27, 2007
• 年：2007
• 卷：46
• 期：8
• 页码：2100 - 2110
• 全文大小：847K
• 年卷期：v.46,no.8(February 27, 2007)
• ISSN：1520-4995

文摘

Human brahma-related gene 1 (Brg1) is a core protein in human SWI/SNF chromatin-remodeling complex which regulates gene expression. Brg1 contains a bromodomain that has been shownto anchor the entire complex to promoter nucleosomes by interacting with histones that are acetylated atspecific lysine residues. The Brg1 bromodomain belongs to an important subclass of the bromodomainfamily for which no structural information is known. Here we report the solution structure of the Brg1bromodomain determined by NMR. The Brg1 bromodomain conserves the left-handed, four-helix bundletopology found in other bromodomain structures. However, the Z helix of Brg1 bromodomain is about4 residues shorter relative to previously published bromodomain structures. Using NMR perturbationstudies, we demonstrate the Brg1 bromodomain binds acetyllysine in the context of histone tails, with nocomparable affinity for unacetylated peptides. The estimated dissociation constants (K_D) for acetylatedhistone peptides H4-AcK8 and H4-AcK12 are 4.0 and 3.6 mM, respectively. In this study the dominantsubstrate was H3-AcK14 (K_D 1.2 mM). Mutagenesis analysis reveals several residues important forthe binding specificity. Using molecular dynamics simulations, we present a model of the Brg1bromodomain in complex with H3-AcK14 and discuss the potential interactions which provide theselectivity of the Brg1 bromodomain for histone H3-AcK14.