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| | ==The crystal structure of human DNMT1(351-1600)== | | ==The crystal structure of human DNMT1(351-1600)== |
| - | <StructureSection load='4wxx' size='340' side='right' caption='[[4wxx]], [[Resolution|resolution]] 2.62Å' scene=''> | + | <StructureSection load='4wxx' size='340' side='right'caption='[[4wxx]], [[Resolution|resolution]] 2.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wxx]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WXX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WXX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wxx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WXX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WXX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.622Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_(cytosine-5-)-methyltransferase DNA (cytosine-5-)-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.37 2.1.1.37] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4wxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wxx OCA], [http://pdbe.org/4wxx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wxx RCSB], [http://www.ebi.ac.uk/pdbsum/4wxx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wxx ProSAT]</span></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=4wxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wxx OCA], [https://pdbe.org/4wxx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wxx RCSB], [https://www.ebi.ac.uk/pdbsum/4wxx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wxx ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN]] Defects in DNMT1 are the cause of hereditary sensory neuropathy type 1E (HSN1E) [MIM:[http://omim.org/entry/614116 614116]]. A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.<ref>PMID:21532572</ref> | + | [https://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN] Defects in DNMT1 are the cause of hereditary sensory neuropathy type 1E (HSN1E) [MIM:[https://omim.org/entry/614116 614116]. A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.<ref>PMID:21532572</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN]] Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.<ref>PMID:16357870</ref> <ref>PMID:18754681</ref> <ref>PMID:18413740</ref> | + | [https://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN] Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.<ref>PMID:16357870</ref> <ref>PMID:18754681</ref> <ref>PMID:18413740</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | DNMT1 (DNA methyltransferase 1) is responsible for propagating the DNA methylation patterns during DNA replication. DNMT1 contains, in addition to a C-terminal methyltransferase domain, a large N-terminal regulatory region that is composed of an RFTS (replication foci targeting sequence) domain, a CXXC zinc finger domain and a pair of BAH (bromo adjacent homology) domains. The regulatory domains of DNMT1 mediate a network of protein-protein and protein-DNA interactions to control the recruitment and enzymatic activity of DNMT1. Here we report the crystal structure of human DNMT1 with all the structural domains (hDNMT1, residues 351-1600) in complex with S-adenosyl-l-homocysteine at 2.62A resolution. The RFTS domain directly associates with the methyltransferase domain, thereby inhibiting the substrate binding of hDNMT1. Through structural analysis, mutational, biochemical and enzymatic studies, we further identify that a linker sequence between the CXXC and BAH1 domains, aside from its role in the CXXC domain-mediated DNMT1 autoinhibition, serves as an important regulatory element in the RFTS domain-mediated autoinhibition. In comparison with the previously determined structure of mouse DNMT1, this study also reveals a number of distinct structural features that may underlie subtle functional diversity observed for the two orthologues. In addition, this structure provides a framework for understanding the functional consequence of disease-related hDNMT1 mutations.
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| - | | + | |
| - | Crystal Structure of Human DNA Methyltransferase 1.,Zhang ZM, Liu S, Lin K, Luo Y, Perry JJ, Wang Y, Song J J Mol Biol. 2015 Jun 10. pii: S0022-2836(15)00341-1. doi:, 10.1016/j.jmb.2015.06.001. PMID:26070743<ref>PMID:26070743</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4wxx" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[DNA methyltransferase|DNA methyltransferase]] | + | *[[DNA methyltransferase 3D structures|DNA methyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Song, J]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Zhang, Z M]] | + | [[Category: Large Structures]] |
| - | [[Category: Dna methylation]] | + | [[Category: Song J]] |
| - | [[Category: Dna methytransferase1]] | + | [[Category: Zhang ZM]] |
| - | [[Category: Dnmt1]]
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| - | [[Category: Transferase]]
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| Structural highlights
Disease
DNMT1_HUMAN Defects in DNMT1 are the cause of hereditary sensory neuropathy type 1E (HSN1E) [MIM:614116. A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.[1]
Function
DNMT1_HUMAN Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.[2] [3] [4]
See Also
References
- ↑ Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011 Jun;43(6):595-600. Epub 2011 May 1. PMID:21532572 doi:10.1038/ng.830
- ↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
- ↑ Pradhan M, Esteve PO, Chin HG, Samaranayke M, Kim GD, Pradhan S. CXXC domain of human DNMT1 is essential for enzymatic activity. Biochemistry. 2008 Sep 23;47(38):10000-9. doi: 10.1021/bi8011725. Epub 2008 Aug, 29. PMID:18754681 doi:10.1021/bi8011725
- ↑ Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726
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