Insight into the Architecture of the NuRD Complex

AlQarni, Saad; Murthy, Andal; Zhang, Wei; Przewloka, Marcin R.; Silva, Ana P. G.; Watson, Aleksandra A.; Lejon, Sara; Pei, X.Y.; Smits, Arne H.; Kloet, Susan L.; Wang, Hongxin; Shepherd, Nicholas E.; Stokes, Philippa H.; Blobel, Gerd A.; Vermeulen, Michiel; Glover, David M.; Mackay, Joel P.; Laue, Ernest D.

doi:10.1074/jbc.m114.558940

Cited by 74 publications

(112 citation statements)

References 64 publications

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“…15 This sequence encompasses a helical 678 KRAARR motif (an RBBP-binding motif, or RBM) that forms a number of electrostatic interactions with the RBBP partner. Examination of the MTA1 sequence revealed a second RBM with a closely related sequence that is highly conserved across complex eukaryotes [Figs.…”

Section: Resultsmentioning

confidence: 99%

“…We identified 58 high-confidence crosslinks (Supporting Information Table I). Amongst these 58 crosslinks, 13 could be mapped to our previously determined crystal structure of RBBP4 bound to MTA1 670-695 (15), including RBBP4 K22 -MTA1 K686 , RBBP4 K317 -MTA1 K686 , and RBBP4-RBBP4 intra-protein crosslinks. Importantly, all 13 of these crosslinks were within the maximum distance limits for the crosslinker used, providing confidence in the XL-MS data.…”

Section: Covalent Crosslinking Combined With Mass Spectrometry (Xl-ms)mentioning

confidence: 99%

“…The RBBP4-MTA1 449-715 model was generated by fitting the RBBP4 crystallographic dimer from 4PBY 15 into the output EM envelope using the "fit in map" function of the CHIMERA software. 28 A series of bioinformatics tools were used to analyse the MTA1 491-499 sequence and guide modeling.…”

Section: Modeling Of the Rbbp4-mta1 449-715 Complexmentioning

confidence: 99%

“…1(B)] include an HDAC1-MTA1 dimer of dimers involving the ELM and SANT domains of MTA1 14 and a complex formed between RBBP4 and a short motif at the C-terminal end of MTA1. 15 As part of efforts to delineate the architecture of the NuRD complex, we have examined the interaction between RBBP-and MTA-family proteins and we show here that MTA1 and -2 carry two motifs that can each independently recruit a molecule of RBBP4. In vitro binding studies show that these two interactions can occur simultaneously and negativestain single particle electron microscopy combined with covalent crosslinking and mass spectrometry (XL-MS) reveals the overall shape of an MTA1:(RBBP4) 2 subcomplex.…”

Section: Introductionmentioning

confidence: 99%

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The MTA1 subunit of the nucleosome remodeling and deacetylase complex can recruit two copies of RBBP4/7

et al. 2016

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The nucleosome remodeling and deacetylase (NuRD) complex remodels the genome in the context of both gene transcription and DNA damage repair. It is essential for normal development and is distributed across multiple tissues in organisms ranging from mammals to nematode worms. In common with other chromatin-remodeling complexes, however, its molecular mechanism of action is not well understood and only limited structural information is available to show how the complex is assembled. As a step towards understanding the structure of the NuRD complex, we have characterized the interaction between two subunits: the metastasis associated protein MTA1 and the histone-binding protein RBBP4. We show that MTA1 can bind to two molecules of RBBP4 and present negative stain electron microscopy and chemical crosslinking data that allow us to build a low-resolution model of an MTA1-(RBBP4) 2 subcomplex. These data build on our understanding of NuRD complex structure and move us closer towards an understanding of the biochemical basis for the activity of this complex.

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Section: Resultsmentioning

confidence: 99%

Section: Covalent Crosslinking Combined With Mass Spectrometry (Xl-ms)mentioning

confidence: 99%

Section: Modeling Of the Rbbp4-mta1 449-715 Complexmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The MTA1 subunit of the nucleosome remodeling and deacetylase complex can recruit two copies of RBBP4/7

et al. 2016

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“…RbAp46 and RbAp48 (pRB-associated proteins p46 and p48, also known as RBBP7 and RBBP4, respectively) are highly homologous histone chaperones that play key roles in establishing and maintaining chromatin structure [23][24][25] . Although RbAp46/48 proteins are not required for the HMTase activity of EZH2 and do not appear to stimulate it, they have important PRC2-related function [26] .…”

Section: Introductionmentioning

confidence: 99%

Structure of the PRC2 complex and application to drug discovery

et al. 2017

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The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

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PRC2‐complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes

Cyrus

Burkardt

Weaver

et al. 2019

American J of Med Genetics Pt C

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The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic “writer” with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss‐of‐function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2‐associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED‐associated overgrowth (Cohen–Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.

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Insight into the Architecture of the NuRD Complex

Cited by 74 publications

References 64 publications

The MTA1 subunit of the nucleosome remodeling and deacetylase complex can recruit two copies of RBBP4/7

The MTA1 subunit of the nucleosome remodeling and deacetylase complex can recruit two copies of RBBP4/7

Structure of the PRC2 complex and application to drug discovery

PRC2‐complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes

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