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Structure and Function of the BAH Domain in Chromatin Biology

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Structure and Function of the BAH Domain in Chromatin Biology http://informahealthcare.com/bmg ISSN: 1040-9238 (print), 1549-7798 (electronic) Editor: Michael M. Cox Crit Rev Biochem Mol Biol, 2013; 48(3): 211–221 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/10409238.2012.742035 REVIEW ARTICLE Structure and function of the BAH domain in chromatin biology Na Yang and Rui-Ming Xu National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Abstract Keywords Proteins containing Bromo Adjacent Homology (BAH) domain are often associated with DNA replication, histone modification, biological processes involving chromatin, and mutations in BAH domains have been found in nucleosome remodeling, protein–protein human diseases. A number of structural and functional studies have revealed that the BAH interaction, structure, transcriptional domain plays diverse and versatile roles in chromatin biology, including protein–protein silencing interactions, recognition of methylated histones and nucleosome binding. Here we review recent developments in structural studies of the BAH domain, and intend to place the structural History results in the context of biological functions of the BAH domain-containing proteins. A converging theme from the structural studies appears that the predominantly b-sheet fold Received 28 August 2012 of the BAH domain serves as a scaffold, and function-specific structural features are Revised 17 October 2012 incorporated at the loops connecting the b-strands and surface-exposed areas. The structures Accepted 17 October 2012 clearly specified regions critical for protein–protein interactions, located the position of Published online 27 November 2012 methyllysine-binding site and implicated areas important for nucleosome binding. The structural results provided valuable insights into the molecular mechanisms of BAH domains in molecular recognitions, and the information should greatly facilitate mechanistic under- standing of BAH domain proteins in chromatin biology. Introduction SNF-like chromatin-remodeling complex (Wang et al., 1996a, 1996b; Thompson, 2009). The yeast RSC chromatin-remo- The term Bromo Adjacent Homology (BAH) domain was deling complex has two BAH domain-containing subunits, coined in 1996 by an analysis of domain structures of the RSC1 and RSC2 (Cairns et al., 1996, 1999). Many BAH chicken polybromo (gPB) protein (Nicolas & Goodwin, domains are present together with domains frequently 1996). Polybromo contains six tandem bromo domains at associated with nuclear functions, such as Bromo, SANT the N-terminus half, followed by two repeated sequence and PHD domains, which are known to bind histones or DNA. motifs of unknown functions, thus called BAH domains, and a A schematic diagram showing major classes of BAH domain HMG DNA-binding box near the C-terminal end (Figure 1). proteins are shown in Figure 1. Further sequence analyses extended the original definition of Early analyses suggested that the BAH domain might be a the BAH domain from an 85 residue motif to one with protein–protein interaction module, but little was known 120–140 residues, and revealed the broad presence of the about its interaction partners and mode of interactions BAH domain in proteins associated with chromatin processes (Callebaut et al., 1999; Goodwin & Nicolas, 2001; Zhang in species ranging from yeasts to mammals (Callebaut et al., et al., 2002). Recent developments, notably from structural 1999; Goodwin & Nicolas, 2001). At present, SMART 2013 studies, have significantly advanced understandings of the protein domain database tabulated 1082 BAH domains in molecular mechanisms of BAH domains, particularly in areas 903 proteins, which include five proteins in Saccharomyces of epigenetic inheritance and gene regulation. This review is cerevisiae, four in Caenorhabditis elegans, eight in intended to provide an overview of the structural findings and Drosophila,26inArabidopsis, 21 in mouse and 19 proteins to place the structural results in the context of biological in human (http://smart.embl-heidelberg.de/). Most of the functions of the BAH domain-containing proteins. characterized BAH domain proteins have clear connections to chromatin processes, such as nucleosome-remodeling, histone and DNA modifications. The human ortholog of Overall structure polybromo, BAF180/PB1, is a component of PBAF, a SWI/ To date, six BAH domain structures have been determined (Figure 2). They are the BAH domains of yeast and mouse Orc1 (Zhang et al., 2002; Hou et al., 2005; Hsu et al., 2005; Address for Correspondence: Rui-Ming Xu or Na Yang, National Kuo et al., 2012), yeast Sir3 (Connelly et al., 2006; Hou Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. E-mail: rmxu@sun5. et al., 2006), the first BAH domain of gPB (Oliver et al., ibp.ac.cn; [email protected] 2005) and the tandem BAH domains (BAH1 and BAH2) 212 N. Yang & R.-M. Xu Crit Rev Biochem Mol Biol, 2013; 48(3): 211–221 Figure 1. Schematic diagram showing domain structures of representative BAH domain-containing proteins. Shapes and colors indicating different types of domains are annotated at the bottom of the figure. Protein names are indicated on the left, and the drawings are approximately in scale with the length of the protein. (see colour version of this figure online at www.informahealthcare/bbm). of mouse DNMT1 (Song et al., 2011, 2012; Takeshita silencing functions, demonstrating that the BAH domain et al., 2011) (Figure 2). The yeast Orc1 (yOrc1) BAH alone is sufficient for Sir1-dependent silencing (Triolo & structure was the first to be solved (Zhang et al., 2002). Orc1 Sternglanz, 1996). is the largest subunit of the six-subunit origin recognition The structure of the BAH domain of yOrc1 shows that the complex (ORC), which functions in the initiation of DNA structurally defined region encompasses residues 1–215, with replication and transcriptional silencing (Bell & Stillman, a disordered internal loop spanning residues 23–36 (Zhang 1992; Bell et al., 1993; Fox et al., 1995, 1997; Loo et al., et al., 2002). The BAH domain has a predominantly b-sheet 1995). The BAH domain of yOrc1 is not required for DNA core composed of 10 b-strands, b1–b10 (Figure 2A). Two replication, but later studies show that it is important for the long antiparallel strands, b5 and b6, together with b4 and b7 association of the ORC complex with chromatin and form a central b-sheet. b7 is highly twisted, and in some BAH regulation of the origin activity (Bell et al., 1995; Lipford domains it breaks into two short strands (Figure 2D and E). & Bell, 2001; Noguchi et al., 2006; Eaton et al., 2010; Muller b1–b3 form a separate sheet and pack against the central et al., 2010). The BAH domain of yOrc1 functions in b-sheet at one end of the central b-sheet near the b5-turn-b6 transcriptional silencing of the mating-type (HM) loci, which region, with the two sets of b-strands are approximately are flanked by DNA elements, are known as silencers. perpendicular to each other. Parallel strands b8 and b9 form Silencer-bound ORC complexes interact with Sir1, which a sheet with a short strand, b10, and together with a small a recruits the Sir2-Sir4 histone deacetylase complex via inter- helix (aE), pack against the central b-sheet on the same action with Sir4 (Chien et al., 1993; Triolo & Sternglanz, side of the b-sheet surface, but at the end distal to the one 1996; Gardner et al., 1999; Bose et al., 2004). Sir4 can occupied by the b1–b3 sheet (Figure 2A). A pair of helices simultaneously interact with Sir3, leading to the assembly of at the C terminus pack against the middle portion of the the Sir2–Sir3–Sir4 complex required for silencing the HM central b-sheet. Finally, a small, independently folded, loci (Rusche et al., 2003). Hence, the silencer-bound ORC non-conserved helical domain (H-domain) is inserted complex confers Sir1-dependent silencing via the BAH between b6 and b7. domain of yOrc1. In fact, an isolated BAH domain of Only the central b-sheet is common among all BAH yOrc1 targeted to an artificial silencer via the Gal4 domains, while N- and C-terminal extensions, and the DNA-binding domain is capable of achieving similar H-domain are distinct (Figure 2). The conserved residues DOI: 10.3109/10409238.2012.742035 BAH domains 213 Figure 2. 3D structures of BAH domains. All six BAH domain structures known to date are shown in (A)–(F). The conserved b-sheet core is colored green, the common insertion region (H-domain) between b6 and b7 is colored magenta and auxiliary regions are colored grey. (see colour version of this figure online at www.informahealthcare/bbm). among the BAH domains are mostly involved in protein experiments indicate that the non-conserved H-domain within folding, suggesting that the BAH domain serves as a scaffold the BAH domain is important for Sir1 binding (Zhang et al., for harboring structural features with specific functions. 2002). The cocrystal structure shows that Sir1 OID is bound in a shallow groove formed between the b-sheet core and the non-conserved H-domain of yOrc1 BAH domain (Hou et al., BAH domain as a scaffold for protein–protein 2005; Hsu et al., 2005) (Figure 3). The three yOrc1 regions interaction contacting Sir1 OID are: (I) the loop connecting b6 and the Sir1 is the first BAH domain-binding partner identified. The first helix (aB) of the H-domain, (II) the third helix (aD) of Orc1-binding domain (OID) of Sir1 maps to an approximately the H-domain and (III) the b4–b5 turn region of the b-sheet 130-residue region near the C-terminus (Triolo & Sternglanz, core. Sir1 OID is composed of two juxtaposed subdomains 1996; Gardner et al., 1999; Bose et al., 2004). Structure- rich in b-strands. The N-terminal subdomain is involved in guided mutagenesis, GST-pull down and yeast two hybrid contacting the BAH domain of yOrc1.
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