7o45

From Proteopedia

(Difference between revisions)

Revision as of 06:23, 26 October 2022

Crystal structure of ADD domain of the human DNMT3B methyltransferase

Structural highlights

7o45 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DNM3B_HUMAN ICF syndrome. The disease is caused by mutations affecting the gene represented in this entry.^[1] ^[2] ^[3] ^[4] ^[5]

Function

DNM3B_HUMAN Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 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. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Function as transcriptional corepressor by associating with ZHX1.^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

De novo DNA methylation in early mammalian development depends on the activity of the DNMT3 methyltransferase family. An autoinhibitory mechanism involving the interaction between ADD and the catalytic domains of DNMT3A has been described. ADD is a zinc-coordinating histone-binding domain. The ADD domain of DNMT3A, when bound to a K4-unmethylated histone H3 tail, switches the enzyme to its catalytically active state. DNMT3B is another de novo methyltransferase enzyme with a more strict tissue- and stage-specific expression profile and a slightly different site specificity, lacking cooperative DNA methylation activity. Here, we obtained the crystal structure of the DNMT3B ADD domain, which demonstrated the extended conformation of the autoinhibitory loop even in the absence of the histone H3 tail. The lack of interaction between DNMT3B ADD and the methyltransferase domain was confirmed using an in vitro pull-down assay. The structural rearrangements in the loop also created an additional protein interaction interface leading to the formation of trimers in crystal, which may reflect their possible involvement in some unknown protein-protein interactions. Our results suggest that DNMT3B, in contrast to DNMT3A, has different modes of regulation of its activity that are independent of H3K4 methylation status.

Structure of the DNMT3B ADD domain suggests the absence of a DNMT3A-like autoinhibitory mechanism.,Boyko K, Arkova O, Nikolaeva A, Popov VO, Georgiev P, Bonchuk A Biochem Biophys Res Commun. 2022 Sep 3;619:124-129. doi:, 10.1016/j.bbrc.2022.06.036. Epub 2022 Jun 18. PMID:35760008^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999 Nov 11;402(6758):187-91. PMID:10647011 doi:http://dx.doi.org/10.1038/46052
↑ Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999 Oct 29;99(3):247-57. PMID:10555141
↑ Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14412-7. PMID:10588719
↑ Wijmenga C, Hansen RS, Gimelli G, Bjorck EJ, Davies EG, Valentine D, Belohradsky BH, van Dongen JJ, Smeets DF, van den Heuvel LP, Luyten JA, Strengman E, Weemaes C, Pearson PL. Genetic variation in ICF syndrome: evidence for genetic heterogeneity. Hum Mutat. 2000 Dec;16(6):509-17. PMID:11102980 doi:<509::AID-HUMU8>3.0.CO;2-V http://dx.doi.org/10.1002/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V
↑ Jiang YL, Rigolet M, Bourc'his D, Nigon F, Bokesoy I, Fryns JP, Hulten M, Jonveaux P, Maraschio P, Megarbane A, Moncla A, Viegas-Pequignot E. DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat. 2005 Jan;25(1):56-63. PMID:15580563 doi:http://dx.doi.org/10.1002/humu.20113
↑ 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
↑ Kim SH, Park J, Choi MC, Kim HP, Park JH, Jung Y, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY. Zinc-fingers and homeoboxes 1 (ZHX1) binds DNA methyltransferase (DNMT) 3B to enhance DNMT3B-mediated transcriptional repression. Biochem Biophys Res Commun. 2007 Apr 6;355(2):318-23. Epub 2007 Feb 8. PMID:17303076 doi:http://dx.doi.org/10.1016/j.bbrc.2007.01.187
↑ 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
↑ Kim SH, Park J, Choi MC, Park JH, Kim HP, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY. DNA methyltransferase 3B acts as a co-repressor of the human polycomb protein hPc2 to repress fibroblast growth factor receptor 3 transcription. Int J Biochem Cell Biol. 2008;40(11):2462-71. doi: 10.1016/j.biocel.2008.04.018. , Epub 2008 May 18. PMID:18567530 doi:http://dx.doi.org/10.1016/j.biocel.2008.04.018
↑ Boyko K, Arkova O, Nikolaeva A, Popov VO, Georgiev P, Bonchuk A. Structure of the DNMT3B ADD domain suggests the absence of a DNMT3A-like autoinhibitory mechanism. Biochem Biophys Res Commun. 2022 Sep 3;619:124-129. doi:, 10.1016/j.bbrc.2022.06.036. Epub 2022 Jun 18. PMID:35760008 doi:http://dx.doi.org/10.1016/j.bbrc.2022.06.036

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7o45"

@@ Line 1: / Line 1: @@
 ==Crystal structure of ADD domain of the human DNMT3B methyltransferase==
-<StructureSection load='7o45' size='340' side='right'caption='[[7o45]]' scene=''>
+<StructureSection load='7o45' size='340' side='right'caption='[[7o45]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7O45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O45 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7o45]] is a 4 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=7O45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O45 FirstGlance]. <br>
-</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=7o45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o45 OCA], [https://pdbe.org/7o45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o45 RCSB], [https://www.ebi.ac.uk/pdbsum/7o45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o45 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</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'>[https://proteopedia.org/fgij/fg.htm?mol=7o45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o45 OCA], [https://pdbe.org/7o45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o45 RCSB], [https://www.ebi.ac.uk/pdbsum/7o45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o45 ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/DNM3B_HUMAN DNM3B_HUMAN] ICF syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:10647011</ref> <ref>PMID:10555141</ref> <ref>PMID:10588719</ref> <ref>PMID:11102980</ref> <ref>PMID:15580563</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/DNM3B_HUMAN DNM3B_HUMAN] Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 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. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Function as transcriptional corepressor by associating with ZHX1.<ref>PMID:16357870</ref> <ref>PMID:17303076</ref> <ref>PMID:18413740</ref> <ref>PMID:18567530</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+De novo DNA methylation in early mammalian development depends on the activity of the DNMT3 methyltransferase family. An autoinhibitory mechanism involving the interaction between ADD and the catalytic domains of DNMT3A has been described. ADD is a zinc-coordinating histone-binding domain. The ADD domain of DNMT3A, when bound to a K4-unmethylated histone H3 tail, switches the enzyme to its catalytically active state. DNMT3B is another de novo methyltransferase enzyme with a more strict tissue- and stage-specific expression profile and a slightly different site specificity, lacking cooperative DNA methylation activity. Here, we obtained the crystal structure of the DNMT3B ADD domain, which demonstrated the extended conformation of the autoinhibitory loop even in the absence of the histone H3 tail. The lack of interaction between DNMT3B ADD and the methyltransferase domain was confirmed using an in vitro pull-down assay. The structural rearrangements in the loop also created an additional protein interaction interface leading to the formation of trimers in crystal, which may reflect their possible involvement in some unknown protein-protein interactions. Our results suggest that DNMT3B, in contrast to DNMT3A, has different modes of regulation of its activity that are independent of H3K4 methylation status.
+Structure of the DNMT3B ADD domain suggests the absence of a DNMT3A-like autoinhibitory mechanism.,Boyko K, Arkova O, Nikolaeva A, Popov VO, Georgiev P, Bonchuk A Biochem Biophys Res Commun. 2022 Sep 3;619:124-129. doi:, 10.1016/j.bbrc.2022.06.036. Epub 2022 Jun 18. PMID:35760008<ref>PMID:35760008</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7o45" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Bonchuk AN]]

7o45

From Proteopedia

Revision as of 06:23, 26 October 2022

Crystal structure of ADD domain of the human DNMT3B methyltransferase

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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