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| | ==MBD2 in complex with methylated DNA== | | ==MBD2 in complex with methylated DNA== |
| - | <StructureSection load='6cnq' size='340' side='right' caption='[[6cnq]], [[Resolution|resolution]] 2.15Å' scene=''> | + | <StructureSection load='6cnq' size='340' side='right'caption='[[6cnq]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cnq]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6c2e 6c2e]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CNQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cnq]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6c2e 6c2e]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CNQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.151Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=5CM:5-METHYL-2-DEOXY-CYTIDINE-5-MONOPHOSPHATE'>5CM</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5CM:5-METHYL-2-DEOXY-CYTIDINE-5-MONOPHOSPHATE'>5CM</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MBD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6cnq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnq OCA], [https://pdbe.org/6cnq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cnq RCSB], [https://www.ebi.ac.uk/pdbsum/6cnq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnq ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cnq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnq OCA], [http://pdbe.org/6cnq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cnq RCSB], [http://www.ebi.ac.uk/pdbsum/6cnq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnq ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MBD2_HUMAN 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.<ref>PMID:10471499</ref> <ref>PMID:10947852</ref> <ref>PMID:12665568</ref> <ref>PMID:16415179</ref> <ref>PMID:24307175</ref> <ref>PMID:9774669</ref> | + | [https://www.uniprot.org/uniprot/MBD2_HUMAN 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.<ref>PMID:10471499</ref> <ref>PMID:10947852</ref> <ref>PMID:12665568</ref> <ref>PMID:16415179</ref> <ref>PMID:24307175</ref> <ref>PMID:9774669</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6cnq" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cnq" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Methyl CpG binding protein 3D structures|Methyl CpG binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Liu, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Min, J]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Structural genomic]] | + | [[Category: Liu K]] |
| - | [[Category: Xu, C]] | + | [[Category: Min J]] |
| - | [[Category: Dna binding]] | + | [[Category: Xu C]] |
| - | [[Category: Dna methylation]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Cytosine methylation is a well characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-containing DNAs, are recognized by methyl-CpG-binding protein 2 (MeCP2) to regulate gene expression in neuron development. However, the molecular mechanism involved in the binding of methyl-CpG-binding domain (MBD) of MeCP2 to these different DNA motifs is unclear. Here, we systematically characterized the DNA-binding selectivity of the MBDs in MeCP2 and MBD1-4 with isothermal titration calorimetry-based binding assays, mutagenesis studies, and X-ray crystallography. We found that the MBD domains of MeCP2 and MBD1-4<br />bind mCG-containing DNAs independently of the sequence outside the mCG dinucleotide. Moreover, some 1 MBDs bound to both methylated and unmethylated CA dinucleotide-<br />containing DNAs, with a preference for the CAC sequence motif. We also found that MBD domains bind to mCA or nonmethylated CA DNA by recognizing the complementary TG dinucleotide, which is consistent with an overlooked ligand of MeCP2, i.e., the matrix/scaffold attachment regions (MARs/SARs) with a consensus sequence of 5'-GGTGT-3', which was<br />identified in early 1990s. Our results also explain why MeCP2 exhibits similar binding affinity to both mCAand hmCA-containing dsDNAs. In summary, our results suggest that in addition to mCG sites, unmethylated CA or TG sites also serve as DNA-binding sites for MeCP2 and other MBDcontaining proteins. This discovery expands the genome-wide activity of MBD-containing proteins in gene regulation.
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 Mar 22. pii: RA118.001785. doi: 10.1074/jbc.RA118.001785. PMID:29567833[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Liu K, Xu C, Lei M, Yang A, Loppnau P, Hughes TR, Min J. Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA. J Biol Chem. 2018 Mar 22. pii: RA118.001785. doi: 10.1074/jbc.RA118.001785. PMID:29567833 doi:http://dx.doi.org/10.1074/jbc.RA118.001785
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