The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture

Low, Jason K. K.; Silva, Ana P. G.; Tabar, Mehdi Sharifi; Torrado, Mario; Webb, Sarah R.; Parker, Benjamin L.; Sana, Maryam; Smits, C.; Schmidberger, J.W.; Brillault, Lou; Jackman, Matthew J.; Williams, David C.; Blobel, Gerd A.; Hake, Sandra B.; Shepherd, Nicholas E.; Landsberg, Michael J.; Mackay, Joel P.

doi:10.1016/j.celrep.2020.108450

Cited by 42 publications

(105 citation statements)

References 81 publications

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“…6A). The 2:2:4 ratios for MHR exactly matches the previous crystal and NMR structures [18], as well as MS quantifications [35,11,6,34]. Similarly, when GATAD2B was used as bait, the ratio for the MHR module remained constant (2:2:4) but we calculated a ratio of ~2:1:2 for MBD:CHD:CDK2AP1 (Fig.…”

Section: Fixed and Altered Stoichiometries Was Observed For Mhr And Mgcc Modules Respectivelysupporting

confidence: 83%

“…This ~1 MDa nuclear protein complex harbours both chromatin remodeling and lysine deacetylase activities [7,8]. A symmetric module encompassing MTA, HDAC and RBBP proteins (MHR) conveys the lysine deacetylation activity via the HDAC catalytic subunit [8][9][10][11], whereas MBD, GATAD2, CDK2AP1, and CHD proteins (MGCC) collaborate to translocate nucleosomal DNA via the CHD subunit [12,13]. The canonical NuRD complex comprises a stable asymmetric composition of two MHR modules and a single MGCC module [11].…”

Section: Introductionmentioning

confidence: 99%

“…A symmetric module encompassing MTA, HDAC and RBBP proteins (MHR) conveys the lysine deacetylation activity via the HDAC catalytic subunit [8][9][10][11], whereas MBD, GATAD2, CDK2AP1, and CHD proteins (MGCC) collaborate to translocate nucleosomal DNA via the CHD subunit [12,13]. The canonical NuRD complex comprises a stable asymmetric composition of two MHR modules and a single MGCC module [11]. Among other functions, MGCC components regulate the expression of adult globin genes and are linked to β-hemoglobinopathies [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

Tabar

Giardina

Feng

et al. 2021

Preprint

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The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a gene repressor complex. Specific paralogues of the MGCC subunits such as MBD2 and CHD4 are amongst the key repressors of adult-stage fetal globin and provide important targets for molecular therapies in beta (β)-thalassemia. However, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed to date. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms and developing treatment strategies. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.

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Section: Fixed and Altered Stoichiometries Was Observed For Mhr And Mgcc Modules Respectivelysupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

Tabar

Giardina

Feng

et al. 2021

Preprint

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“…Alternatively, MBD2 interactions with methylated DNA could impede the complete assembly of the NuRD complex, resulting in a limited pool of functional complexes. Based on recent crosslinking mass spectrometry and/or structural data and modelling of the complete NuRD complex, MBD proteins have been shown to bridge the HDAC and CHD modules (10)(11)(12). However, if this role, which involves multiple protein-protein interactions with the MBD domain, is compatible with binding to DNA, remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the methyl-CpG binding protein family members MBD2 or MBD3 are essential but mutually exclusive NuRD complex members, therefore assembling distinct MBD2-NuRD or MBD3-NuRD complexes (4,9). Recent structural and biochemical data support the notion that the MBD2 and MBD3 proteins function as a link between the MTA:HDAC:RBBP core and the peripheral GATAD2:CHD:CDK2AP remodeling module (10)(11)(12). Absence of MBD2 or MBD3 therefore disrupts NuRD complex functionality.…”

Section: Introductionmentioning

confidence: 97%

Dissecting the roles of MBD2 isoforms in regulating NuRD complex function during cellular differentiation

Schmolka

Bhaskaran

Karemaker

et al. 2021

Preprint

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The Nucleosome Remodelling and Deacetylation (NuRD) complex is a crucial regulator of cellular differentiation. Two members of the Methyl-CpG-binding domain (MBD) protein family, MBD2 and MBD3, are known to be integral, but mutually exclusive subunits of the NuRD com-plex. Several MBD2 and MBD3 isoforms are present in mammalian cells, resulting in distinct MBD-NuRD complexes. If these different complexes serve distinct biochemical and/or functional activities during differentiation is not completely understood. Based on the essential role of MBD3 in lineage commitment, we systematically investigated a diverse set of MBD3 and MBD2 vari-ants for their potential to rescue the differentiation block observed in mouse embryonic stem cells (ESCs) lacking MBD3. Our study reveals that while MBD3 is indeed crucial for ESC differentiation to neuronal cells, this function is independent of its MBD domain or binding to methylated DNA. While MBD3 isoforms are highly redundant, we identify that MBD2 isoforms vary in their potential to fully rescue the absence of MBD3 during lineage commitment. Full-length MBD2a only partially rescues the differentiation block; MBD2b, which lacks the N-terminal GR-rich repeat, fully rescues the differentiation block in MBD3 KO ES cells, and cells expressing the testis-specific isoform MBD2t that lacks the coiled-coil domain required for NuRD interac-tions are not able to generate any differentiated cells. In case of MBD2a, we further show that removing the m-CpG DNA binding capacity or the GR-rich repeat renders the protein fully redundant to MBD3, highlighting the requirements for these domains in diversifying NuRD complex function. In sum, our results highlight a partial redundancy of MBD2 and MBD3 during cellular differentiation and point to specific functions of distinct MBD2 isoforms and specific domains within the NuRD complex.

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Mapping oncogenic protein interactions for precision medicine

Tabar

Francis

Yeo

et al. 2022

Intl Journal of Cancer

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Normal protein-protein interactions (normPPIs) occur with high fidelity to regulate almost every physiological process. In cancer, this highly organised and precisely regulated network is disrupted, hijacked or reprogrammed resulting in oncogenic protein-protein interactions (oncoPPIs). OncoPPIs, which can result from genomic alterations, are a hallmark of many types of cancers. Recent technological advances in the field of mass spectrometry (MS)-based interactomics, structural biology and drug discovery have prompted scientists to identify and characterise oncoPPIs. Disruption of oncoPPI interfaces has become a major focus of drug discovery programs and has resulted in the use of PPI-specific drugs clinically. However, due to several technical hurdles, studies to build a reference oncoPPI map for various cancer types have not been undertaken. Therefore, there is an urgent need for experimental workflows to overcome the existing challenges in studying oncoPPIs in various cancers and to build comprehensive reference maps. Here, we discuss the important hurdles for characterising oncoPPIs and propose a three-phase multidisciplinary workflow to identify and characterise oncoPPIs. Systematic identification of cancertype-specific oncogenic interactions will spur new opportunities for PPI-focused drug discovery projects and precision medicine.

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The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture

Abstract: Highlightsd The NuRD complex has a 4:

Cited by 42 publications

References 81 publications

Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

Dissecting the roles of MBD2 isoforms in regulating NuRD complex function during cellular differentiation

Mapping oncogenic protein interactions for precision medicine

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