Reactome | MBD2, MBD3 and GATAD2A, GATAD2B bind core NuRD complex

MBD2, MBD3 and GATAD2A, GATAD2B bind core NuRD complex

Stable Identifier

R-HSA-9940462

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

3/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

MBD2, MBD3 and GATAD2A, GATAD2B bind core NuRD complex

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

The core deacetylase module of the NuRD complex consisting of HDAC, MTA and RBBP proteins next recruits a sub-module containing, minimally, MDB proteins 2 or 3 and GATAD2A or GATAD2B (Marhold et al, 2004; Brackertz et al, 2002; Brackertz et al, 2006; Gnanapragasam et al, 2011; Kloet et al, 2015; Desai et al, 2015; Spruijt et al, 2021; reviewed in Leighton and Williams, 2020). Some studies indicate that CHD3 or 4 is additionally recruited as part of this module (Low et al, 2020). Crosslinking, interaction and purification studies suggest that overall the complex has a stoichiometry of 4:2:2:1:1 (RBBP:MTA:HDAC:MBD:GATAD2), with the CHD subunit, when present, more loosely associated and sometimes substoichiometric (Tabar et al, 2017; Low et al, 2020). MBD2 and MBD3 are members of a family of methyl-binding domain proteins. MBD2 binds preferentially to methylated CpG islands while MBD3 has similar binding affinity for both methylated and unmethylated DNA (Cramer et al, 2014; Liu et al, 2019; Liu et al, 2018). MBD2 and MBD3 are mutually exclusive in the NuRD complex, with MBD2-containing NuRD complexes more prevalent at sites of repression and those with MBD3 more highly associated with gene activation (Le Guezennec et al, 2006; Gunther et al, 2013; Shimbo et al, 2013; reviewed in Leighton and Williams, 2020). MDB proteins interact with GATAD2A/GATAD2B (also known as p66 alpha and beta, respectively) through a coiled coil region in the GATAD2 proteins (Gnanapragasam et al, 2011; Brackertz et al, 2002; Brackertz et al, 2006; Walavalkar et al, 2013). The function of the GATAD2 proteins in the NuRD complex is not well established, but they appear to play a role in recruiting the CHD component of the complex (Torrado et al, 2017; Zhang et al, 2016; Low et al, 2016; Low et al, 2020; Gnanapragasam et al, 2011; Brackertz et al, 2002; Spruijt et al, 2016; reviewed in Leighton and Williams, 2020). Although some studies indicate that the GATAD proteins may exist as homodimers (Spruijt et al, 2016), that is not depicted in this pathway to be consistent with the consensus on complex stoichiometry. MBD proteins appear to compete for MTA binding with PWWP2A and PWWP2B, chromatin binding proteins that form an alternative complex with the NuRD core, effectively decoupling the NuRD histone deacetylase complex from the ATPase-dependent chromatin repositioning (Zhang et al, 2018; Link et al, 2018; reviewed in Reid et al, 2023).

Literature References

PubMed ID	Title	Journal	Year
27117189	The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules Zhang, W, Aubert, A, Gomez de Segura, JM, Karuppasamy, M, Basu, S, Murthy, AS, Diamante, A, Drury, TA, Balmer, J, Cramard, J, Watson, AA, Lando, D, Lee, SF, Palayret, M, Kloet, SL, Smits, AH, Deery, MJ, Vermeulen, M, Hendrich, B, Klenerman, D, Schaffitzel, C, Berger, I, Laue, ED	J Mol Biol	2016
24385926	MBD3 localizes at promoters, gene bodies and enhancers of active genes Shimbo, T, Du, Y, Grimm, SA, Dhasarathy, A, Mav, D, Shah, RR, Shi, H, Wade, PA	PLoS Genet	2013
33283408	Cross-linking mass spectrometry reveals the structural topology of peripheral NuRD subunits relative to the core complex Spruijt, CG, Gräwe, C, Kleinendorst, SC, Baltissen, MPA, Vermeulen, M	FEBS J	2021
33264611	The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture Low, JKK, Silva, APG, Sharifi Tabar, M, Torrado, M, Webb, SR, Parker, BL, Sana, M, Smits, C, Schmidberger, JW, Brillault, L, Jackman, MJ, Williams, DC, Blobel, GA, Hake, SB, Shepherd, NE, Landsberg, MJ, Mackay, JP	Cell Rep	2020
16428440	MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties le Guezennec, X, Vermeulen, M, Brinkman, AB, Hoeijmakers, WA, Cohen, A, Lasonder, E, Stunnenberg, HG	Mol. Cell. Biol.	2006
25753662	An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex Desai, MA, Webb, HD, Sinanan, LM, Scarsdale, JN, Walavalkar, NM, Ginder, GD, Williams, DC	Nucleic Acids Res	2015
27732854	ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage Spruijt, CG, Luijsterburg, MS, Menafra, R, Lindeboom, RG, Jansen, PW, Edupuganti, RR, Baltissen, MP, Wiegant, WW, Voelker-Albert, MC, Matarese, F, Mensinga, A, Poser, I, Vos, HR, Stunnenberg, HG, van Attikum, H, Vermeulen, M	Cell Rep	2016
31626804	The Methyl-CpG-Binding Domain 2 and 3 Proteins and Formation of the Nucleosome Remodeling and Deacetylase Complex Leighton, G, Williams, DC	J Mol Biol	2020
24307175	Probing the dynamic distribution of bound states for methylcytosine-binding domains on DNA Cramer, JM, Scarsdale, JN, Walavalkar, NM, Buchwald, WA, Ginder, GD, Williams, DC	J Biol Chem	2014
30980593	Structural analyses reveal that MBD3 is a methylated CG binder Liu, K, Lei, M, Wu, Z, Gan, B, Cheng, H, Li, Y, Min, J	FEBS J	2019
30327463	PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex Link, S, Spitzer, RMM, Sana, M, Torrado, M, Völker-Albert, MC, Keilhauer, EC, Burgold, T, Pünzeler, S, Low, JKK, Lindström, I, Nist, A, Regnard, C, Stiewe, T, Hendrich, B, Imhof, A, Mann, M, Mackay, JP, Bartkuhn, M, Hake, SB	Nat Commun	2018
16415179	p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction Brackertz, M, Gong, Z, Leers, J, Renkawitz, R	Nucleic Acids Res	2006
35798615	A NuRD for all seasons Reid, XJ, Low, JKK, Mackay, JP	Trends Biochem Sci	2023
27235397	CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex Low, JK, Webb, SR, Silva, AP, Saathoff, H, Ryan, DP, Torrado, M, Brofelth, M, Parker, BL, Shepherd, NE, Mackay, JP	J Biol Chem	2016
15516265	The Drosophila methyl-DNA binding protein MBD2/3 interacts with the NuRD complex via p55 and MI-2 Marhold, J, Brehm, A, Kramer, K	BMC Mol Biol	2004
12183469	Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3 Brackertz, M, Boeke, J, Zhang, R, Renkawitz, R	J Biol Chem	2002
25123934	Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics Kloet, SL, Baymaz, HI, Makowski, M, Groenewold, V, Jansen, PW, Berendsen, M, Niazi, H, Kops, GJ, Vermeulen, M	FEBS J	2015
30228260	A variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes Zhang, T, Wei, G, Millard, CJ, Fischer, R, Konietzny, R, Kessler, BM, Schwabe, JWR, Brockdorff, N	Nat Commun	2018
29567833	Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA Liu, K, Xu, C, Lei, M, Yang, A, Loppnau, P, Hughes, TR, Min, J	J Biol Chem	2018
23239876	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, NM, Gordon, N, Williams, DC	J Biol Chem	2013
29063705	Refinement of the subunit interaction network within the nucleosome remodelling and deacetylase (NuRD) complex Torrado, M, Low, JKK, Silva, APG, Schmidberger, JW, Sana, M, Sharifi Tabar, M, Isilak, ME, Winning, CS, Kwong, C, Bedward, MJ, Sperlazza, MJ, Williams, DC, Shepherd, NE, Mackay, JP	FEBS J	2017
30828972	The stoichiometry and interactome of the Nucleosome Remodeling and Deacetylase (NuRD) complex are conserved across multiple cell lines Sharifi Tabar, M, Mackay, JP, Low, JKK	FEBS J	2019
21490301	p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex Gnanapragasam, MN, Scarsdale, JN, Amaya, ML, Webb, HD, Desai, MA, Walavalkar, NM, Wang, SZ, Zu Zhu, S, Ginder, GD, Williams, DC	Proc Natl Acad Sci U S A	2011
23361464	Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences Günther, K, Rust, M, Leers, J, Boettger, T, Scharfe, M, Jarek, M, Bartkuhn, M, Renkawitz, R	Nucleic Acids Res	2013