Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Mar 13;432(6):1624-1639.
doi: 10.1016/j.jmb.2019.10.007. Epub 2019 Oct 15.

The Methyl-CpG-Binding Domain 2 and 3 Proteins and Formation of the Nucleosome Remodeling and Deacetylase Complex

Gage Leighton  1 , David C Williams Jr  2
Affiliations
Review

The Methyl-CpG-Binding Domain 2 and 3 Proteins and Formation of the Nucleosome Remodeling and Deacetylase Complex

Gage Leighton et al. J Mol Biol. .

Abstract

The Nucleosome Remodeling and Deacetylase (NuRD) complex uniquely combines both deacetylase and remodeling enzymatic activities in a single macromolecular complex. The methyl-CpG-binding domain 2 and 3 (MBD2 and MBD3) proteins provide a critical structural link between the deacetylase and remodeling components, while MBD2 endows the complex with the ability to selectively recognize methylated DNA. Hence, NuRD combines three major arms of epigenetic gene regulation. Research over the past few decades has revealed much of the structural basis driving formation of this complex and started to uncover the functional roles of NuRD in epigenetic gene regulation. However, we have yet to fully understand the molecular and biophysical basis for methylation-dependent chromatin remodeling and transcription regulation by NuRD. In this review, we discuss the structural information currently available for the complex, the role MBD2 and MBD3 play in forming and recruiting the complex to methylated DNA, and the biological functions of NuRD.

Keywords: Chromatin; DNA methylation; Epigenetics; Histone deacetylase; Nucleosome remodeling.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interest: none

Figures

Figure 1.
Figure 1.. Overview of the NuRD complex.
(a) Schematic diagrams of the seven major NuRD components highlight the domain architecture and relative size of each protein: CDKAP1, MBD2 or 3, RBBP4 or 7, HDAC 1 or 2, GATAD2 A or B, MTA 1, 2, or 3, and CHD 3, 4, or 5. (b) A model of NuRD depicts how these components interact.
Figure 2.
Figure 2.. Structural analyses of the MBD2:GATAD2A and MTA1:HDAC1 complexes
(a) A cartoon diagram depicts the solution structure of the coiled-coil complex between MBD2 (cyan) and GATAD2A (blue) (PBD ID: 2L2L). Amino acids at the protein-protein interface are shown as sticks. (b) A surface rendition of MBD2-CC and GATAD2A colored by electrostatic potential shows alternating patches of positive (blue) and negative (red) regions that promote heterodimerization and minimize homodimerization. (c) A cartoon diagram depicts the crystal structure of the complex between MTA1 (red and light red), HDAC1 (brown and light brown), and a peptide inhibitor (magenta). MTA1 forms a dimer and wraps around HDAC1. An inositol tetraphosphate molecule (space-filled, yellow) binds near the HDAC1 active site. (d) Surface rendering of HDAC1 and MTA1 colored by electrostatic potential shows that IP4 binds to positively charged regions (blue) of each, thereby bridging between surfaces that otherwise would not interact favorably (PDB ID: 5ICN). All structure figures were generated using PyMOL [130] and the electrostatic surface potential using the APBS plugin [131].
Figure 3.
Figure 3.. Binding of MTA1 and FOG1 to RBBP4
A cartoon diagram depicts an overlay of crystal structures showing RBBP4 bound to four different peptides. Two different peptides from MTA1 (amino acids 462–546 in yellow and 670–695 in cyan; PDB ID: 5FXY and 4PBZ, respectively) bind RBBP4 (green) through a common interface. Likewise, the N-terminal helix from histone H4 (amino acids 24–41 in blue; PDB ID: 3CFV) binds to the same region of RBBP4. In contrast, the N-terminal FOG1 peptide (amino acids 1–15 in magenta; PDB ID: 2XU7) binds to a distinct region of RBBP4 that does not overlap with the binding surfaces for MTA1 or histone H4. Note that MTA1 residues not observed in the crystal structure (519–528) are indicated with a yellow dashed line.
Figure 4.
Figure 4.. The intrinsically disordered region and DNA binding domains of MBD2
(a) A schematic diagram of MBD2b (amino acids 214–361) highlights the large intrinsically disordered region located between the N-terminal MBD and C-terminal coiled-coil domain. (b) The intrinsically disordered region (IDR) binds to the HDCC (brown), while mutating two consecutive residues (R286E/L287A, red) disrupts this interaction. (c) An alignment of a region from PWWP2A that binds to the HDCC shows that this peptide shares homology with the MBD2 IDR. This region includes the double-mutation (red) that disrupts MBD2 binding to to the HDCC. (d) A mixed diagram depicts the solution structure of MBD2 (cyan) bound to an mCpG dinucleotide (sticks) (PDB ID: 2KY8). MBD2 makes three key interactions with DNA through a conserved RRY motif. (e) A closeup view shows that arginine residues 24 and 46 each hydrogen bond to symmetrically related guanine bases and pack against methyl groups (orange spheres) of the adjacent methyl-cytosine bases. While tyrosine 36 positions its hydroxyl group towards methyl-cytosine and likely binds to structured water surrounding the methyl group.
Figure 5.
Figure 5.. A model of nucleosome remodeling by the NuRD complex.
A schematic diagram shows a simple model of NuRD function on CpG rich regions of the genome. Given the propensity for MBD2 to bind stably and with high affinity to methylated CpG rich DNA, MBD2-NuRD should reposition nucleosomes away from unmethylated (gray and open circles) and towards densely methylated (black and filled circles) CpG rich regions of the genome. In contrast, MBD3-NuRD would not show the same tendency.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cramer JM, Pohlmann D, Gomez F, Mark L, Kornegay B, Hall C, et al. Methylation specific targeting of a chromatin remodeling complex from sponges to humans. Sci Rep. 2017;7:40674. - PMC - PubMed
    1. Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998;18:6538–47. - PMC - PubMed
    1. Hendrich B, Tweedie S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 2003;19:269–77. - PubMed
    1. Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999;23:58–61. - PubMed
    1. Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998;8:843–6. - PubMed

LinkOut - more resources