Unique Features of the Anti-parallel, Heterodimeric Coiled-coil Interaction between Methyl-cytosine Binding Domain 2 (MBD2) Homologues and GATA Zinc Finger Domain Containing 2A (GATAD2A/p66α)

Walavalkar, Ninad M.; Gordon, Nathaniel C.; Williams, David C.

doi:10.1074/jbc.m112.431346

Cited by 32 publications

(42 citation statements)

References 37 publications

(41 reference statements)

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“…We previously biophysically characterized and determined the structure of a coiled-coil complex formed between vertebrate MBD2 and GATAD2A (p66α), and showed that this interaction was critical for recruitment of CHD4 and methylation-dependent gene silencing by NuRD3435. In the current studies we tested whether the invertebrate coiled-coiled domains from EmMBD2/3 and EmGATAD2A/B could form a similar stable coiled-coil complex.…”

Section: Resultsmentioning

confidence: 92%

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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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Section: Resultsmentioning

confidence: 92%

“…5b), residues involved in direct contact between the two proteins are highly conserved. We previously identified three intermolecular ionic/hydrogen bond interactions critical for high affinity binding3435. The equivalent interactions are maintained in the E. muelleri complex (Fig.…”

Section: Resultsmentioning

confidence: 97%

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

Cramer

Pohlmann

Gomez

et al. 2017

Sci Rep

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“…We also generated a construct, MBD3cc, consisting of murine MBD3 fused to residues 133–174 of mouse GATA2DA (UniProt ID: Q8CHY6 ). This region of GATA2DA has been previously shown to form a coiled-coil interaction with MBD3 [42]. We hypothesised that fusing this region of GATA2DA to MBD3 could stabilise and improve expression of MBD3.…”

Section: Methodsmentioning

confidence: 98%

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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“…Histone-binding proteins Rbbp7 and Rbbp4 (RbAp46 and RbAp48, respectively) bind histone H4 and are thought to function as scaffolding proteins or chaperones which coordinate assembly of multi-protein complexes [25]. Nuclear zinc-finger protein Gata2a and Gata2b (p66α/β) directly interact with MBD2/3 via a coiled-coiled antiparallel interface [26, 27]. While HDAC1/2 and Rbbp7/4 are present in other histone deacetylase co-repressor complexes, such as SIN3 and coREST [28, 29], Mi2, MBD3 and MTA are relatively specific to NuRD and thought to be defining components of this complex.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, development of chemical inhibitors based on this structural information could in principal be tested to treat hemoglobinopathies. The p66α coiled-coil peptide has a similar affinity for MBD3, suggesting that this strategy could also be used to target MBD3-containing NuRD complexes [27]. …”

Section: Introductionmentioning

confidence: 99%

The nucleosome remodeling and deacetylase complex in development and disease

Basta

Rauchman

2015

Translational Research

143

108

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The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis and accelerated ageing. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer.

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Unique Features of the Anti-parallel, Heterodimeric Coiled-coil Interaction between Methyl-cytosine Binding Domain 2 (MBD2) Homologues and GATA Zinc Finger Domain Containing 2A (GATAD2A/p66α)

Cited by 32 publications

References 37 publications

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

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

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

The nucleosome remodeling and deacetylase complex in development and disease

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