An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex

Desai, Megha; Webb, Heather E.; Sinanan, Leander M.; Scarsdale, J.N.; Walavalkar, Ninad M.; Ginder, Gordon D.; Williams, David C.

doi:10.1093/nar/gkv168

Cited by 55 publications

(118 citation statements)

References 70 publications

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“…That is, a core module built around HDAC, MTA, and RBBP subunits carries histone recognition and modification functions, MBD subunits contribute DNA targeting ability, and CHD3/4/5 carries out the remodeling. Such a model is also consistent with data showing that MBD2 binds directly to the HDAC-MTA core complex (45). This idea also raises the possibility that there are other modules that we have yet to learn about, considering that the NuRD complex has been reported to associate with a number of other proteins, including DOC1, ZMYND8, ZNF592, and LSD1 (32,46,47).…”

Section: Discussionsupporting

confidence: 87%

CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex

Low

Webb

Silva

et al. 2016

Journal of Biological Chemistry

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Chromatin remodeling enzymes act to dynamically regulate gene accessibility. In many cases, these enzymes function as large multicomponent complexes that in general comprise a central ATP-dependent Snf2 family helicase that is decorated with a variable number of regulatory subunits. The nucleosome remodeling and deacetylase (NuRD) complex, which is essential for normal development in higher organisms, is one such macromolecular machine. The NuRD complex comprises ϳ10 subunits, including the histone deacetylases 1 and 2 (HDAC1 and HDAC2), and is defined by the presence of a CHD family remodeling enzyme, most commonly CHD4 (chromodomain helicase DNA-binding protein 4). The existing paradigm holds that CHD4 acts as the central hub upon which the complex is built. We show here that this paradigm does not, in fact, hold and that CHD4 is a peripheral component of the NuRD complex. A complex lacking CHD4 that has HDAC activity can exist as a stable species. The addition of recombinant CHD4 to this nucleosome deacetylase complex reconstitutes a NuRD complex with nucleosome remodeling activity. These data contribute to our understanding of the architecture of the NuRD complex.Nucleosomes effectively act as a roadblock to all aspects of genome biology. ATP-dependent chromatin remodeling enzymes solve this problem by using ATP-derived energy to alter the positions, occupancy and composition of nucleosomes. All remodelers possess a highly related ATPase motor domain from the helicase family and are classified into four subfamilies (INO80, ISWI, SWR1, and CHD) based on sequence similarity (1). Each subfamily is represented in nearly all eukaryotes, suggesting that they catalyze different remodeling events. For example, ISWI proteins reposition (or slide) nucleosomes to create regularly spaced arrays; this periodic organization is a key characteristic of DNA at the start of genes (2). SWR1 and INO80 enzymes have opposing roles in histone variant dynamics; the former incorporates these histone variants (e.g. H2A.Z), whereas the latter removes them. These variants set up specific chromatin structures that modulate transcription and replication, although the roles of many variants are still under debate (3). Fundamentally, these remodeling enzymes all alter the accessibility of DNA to other DNA-binding factors and thereby broadly underpin genome biology.Remodelers frequently act in the context of large multisubunit complexes, and in general, the "mixing and matching" of complex composition can generate complexes with varying activities; the human ISWI protein Snf2h for instance has been identified in six distinct complexes (4). Likewise, the accessory subunits can also modulate remodeler activity. For example, the paralogous methyl-CpG-binding domain proteins 2 and 3 (MBD2 and MBD3) subunits of the nucleosome remodeling and deacetylase (NuRD) 6 complex are mutually exclusive (5); MBD2 recognizes 5-methylcytosine-modified DNA, whereas MBD3 instead binds to 5-hydroxymethylated DNA (6, 7). Unsurprisingly, it has been observed tha...

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Section: Discussionsupporting

confidence: 87%

CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex

Low

Webb

Silva

et al. 2016

Journal of Biological Chemistry

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“…[34]) or HDAC1+MTA2N as the prey. For comparison, Figure 4c shows pulldowns using the same proteins co-expressed in HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

“…MBD3cc is a construct that fuses MBD3 with the N-terminal coiled-coil domain of GATAD2A. This latter domain forms a dimer with the MBD3 coiled-coil, stabilizing MBD3 [34]. …”

Section: Figurementioning

confidence: 99%

Refinement of the subunit interaction network within the nucleosome remodelling and deacetylase (NuRD) complex

et al. 2017

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The nucleosome remodelling and deacetylase (NuRD) complex is essential for the development of complex animals. NuRD has roles in regulating gene expression and repairing damaged DNA. The complex comprises at least six proteins with two or more paralogues of each protein routinely identified when the complex is purified from cell extracts. To understand the structure and function of NuRD, a map of direct subunit interactions is needed. Dozens of published studies have attempted to define direct inter-subunit connectivities. We propose that conclusions reported in many such studies are in fact ambiguous for one of several reasons. First, the expression of many NuRD subunits in bacteria is unlikely to lead to folded, active protein. Second, interaction studies carried out in cells that contain endogenous NuRD complex can lead to false positives through bridging of target proteins by endogenous components. Combining existing information on NuRD structure with a protocol designed to minimize false positives, we report a conservative and robust interaction map for the NuRD complex. We also suggest a 3D model of the complex that brings together the existing data on the complex. The issues and strategies discussed herein are also applicable to the analysis of a wide range of multi-subunit complexes.

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“…The remaining regions are predicted to be largely unstructured in isolation and, as such, are poorly conserved. Similarly the MBD2/3 protein contains methyl-cytosine binding (MBD) and coiled-coil (CC) domains separated by an intrinsically disordered region1317. We identified two isoforms of EmMBD2/3, which differ by large insertions within the intrinsically disordered region.…”

Section: Resultsmentioning

confidence: 99%

“…Our laboratory has been studying the structure and function of the methyl-cytosine binding domain (MBD) family of proteins12131415. These proteins share an approximately 60 amino acid domain that can selectively bind to symmetrically methylated CpG dinucleotides.…”

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confidence: 99%

Methylation specific targeting of a chromatin remodeling complex from sponges to humans

Cramer

Pohlmann

Gomez

et al. 2017

Sci Rep

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DNA cytosine methylation and methyl-cytosine binding domain (MBD) containing proteins are found throughout all vertebrate species studied to date. However, both the presence of DNA methylation and pattern of methylation varies among invertebrate species. Invertebrates generally have only a single MBD protein, MBD2/3, that does not always contain appropriate residues for selectively binding methylated DNA. Therefore, we sought to determine whether sponges, one of the most ancient extant metazoan lineages, possess an MBD2/3 capable of recognizing methylated DNA and recruiting the associated nucleosome remodeling and deacetylase (NuRD) complex. We find that Ephydatia muelleri has genes for each of the NuRD core components including an EmMBD2/3 that selectively binds methylated DNA. NMR analyses reveal a remarkably conserved binding mode, showing almost identical chemical shift changes between binding to methylated and unmethylated CpG dinucleotides. In addition, we find that EmMBD2/3 and EmGATAD2A/B proteins form a coiled-coil interaction known to be critical for the formation of NuRD. Finally, we show that knockdown of EmMBD2/3 expression disrupts normal cellular architecture and development of E. muelleri. These data support a model in which the MBD2/3 methylation-dependent functional role emerged with the earliest multicellular organisms and has been maintained to varying degrees across animal evolution.

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An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex

Cited by 55 publications

References 70 publications

CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex

CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex

Refinement of the subunit interaction network within the nucleosome remodelling and deacetylase (NuRD) complex

Methylation specific targeting of a chromatin remodeling complex from sponges to humans

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