| Structural highlights
Function
[P66A_HUMAN] Transcriptional repressor. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2B.[1] [2] [MBD2_HUMAN] Binds CpG islands in promoters where the DNA is methylated at position 5 of cytosine within CpG dinucleotides. Binds hemimethylated DNA as well. Recruits histone deacetylases and DNA methyltransferases. Acts as transcriptional repressor and plays a role in gene silencing. Functions as a scaffold protein, targeting GATAD2A and GATAD2B to chromatin to promote repression. May enhance the activation of some unmethylated cAMP-responsive promoters.[3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Nucleosome remodeling complexes comprise several large families of chromatin modifiers that integrate multiple epigenetic control signals to play key roles in cell type-specific transcription regulation. We previously isolated a methyl-binding domain protein 2 (MBD2)-containing nucleosome remodeling and deacetylation (NuRD) complex from primary erythroid cells and showed that MBD2 contributes to DNA methylation-dependent embryonic and fetal beta-type globin gene silencing during development in vivo. Here we present structural and biophysical details of the coiled-coil interaction between MBD2 and p66alpha, a critical component of the MBD2-NuRD complex. We show that enforced expression of the isolated p66alpha coiled-coil domain relieves MBD2-mediated globin gene silencing and that the expressed peptide interacts only with a subset of components of the MBD2-NuRD complex that does not include native p66alpha or Mi-2. These results demonstrate the central importance of the coiled-coil interaction and suggest that MBD2-dependent DNA methylation-driven gene silencing can be disrupted by selectively targeting this coiled-coil complex.
p66{alpha}-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, Zhu SZ, Ginder GD, Williams DC Jr Proc Natl Acad Sci U S A. 2011 Apr 13. PMID:21490301[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brackertz M, Boeke J, Zhang R, Renkawitz R. Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3. J Biol Chem. 2002 Oct 25;277(43):40958-66. Epub 2002 Aug 14. PMID:12183469 doi:http://dx.doi.org/10.1074/jbc.M207467200
- ↑ Brackertz M, Gong Z, Leers J, Renkawitz R. p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic Acids Res. 2006 Jan 13;34(2):397-406. Print 2006. PMID:16415179 doi:http://dx.doi.org/10.1093/nar/gkj437
- ↑ Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999 Sep;23(1):58-61. PMID:10471499 doi:http://dx.doi.org/10.1038/12659
- ↑ Tatematsu KI, Yamazaki T, Ishikawa F. MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase. Genes Cells. 2000 Aug;5(8):677-88. PMID:10947852
- ↑ Fujita H, Fujii R, Aratani S, Amano T, Fukamizu A, Nakajima T. Antithetic effects of MBD2a on gene regulation. Mol Cell Biol. 2003 Apr;23(8):2645-57. PMID:12665568
- ↑ Brackertz M, Gong Z, Leers J, Renkawitz R. p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic Acids Res. 2006 Jan 13;34(2):397-406. Print 2006. PMID:16415179 doi:http://dx.doi.org/10.1093/nar/gkj437
- ↑ Cramer JM, Scarsdale JN, Walavalkar NM, Buchwald WA, Ginder GD, Williams DC Jr. Probing the Dynamic Distribution of Bound States for Methyl-cytosine Binding Domains on DNA. J Biol Chem. 2013 Dec 4. PMID:24307175 doi:http://dx.doi.org/10.1074/jbc.M113.512236
- ↑ Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998 Nov;18(11):6538-47. PMID:9774669
- ↑ Gnanapragasam MN, Scarsdale JN, Amaya ML, Webb HD, Desai MA, Walavalkar NM, Wang SZ, Zhu SZ, Ginder GD, Williams DC Jr. p66{alpha}-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc Natl Acad Sci U S A. 2011 Apr 13. PMID:21490301 doi:10.1073/pnas.1015341108
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