5ciu

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Structural basis of the recognition of H3K36me3 by DNMT3B PWWP domainStructural basis of the recognition of H3K36me3 by DNMT3B PWWP domain

Structural highlights

5ciu 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.
Method:X-ray diffraction, Resolution 2.24Å
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

DNA methylation is an important epigenetic modification involved in chromatin organization and gene expression. The function of DNA methylation depends on cell context and is correlated with histone modification patterns. In particular, trimethylation of Lys36 on histone H3 tail (H3K36me3) is associated with DNA methylation and elongation phase of transcription. PWWP domains of the de novo DNA methyltransferases DNMT3A and DNMT3B read this epigenetic mark to guide DNA methylation. Here we report the first crystal structure of the DNMT3B PWWP domain-H3K36me3 complex. Based on this structure, we propose a model of the DNMT3A PWWP domain-H3K36me3 complex and build a model of DNMT3A (PWWP-ADD-CD) in a nucleosomal context. The trimethylated side chain of Lys36 (H3K36me3) is inserted into an aromatic cage similar to the "Royal" superfamily domains known to bind methylated histones. A key interaction between trimethylated Lys36 and a conserved water molecule stabilized by Ser270 explains the lack of affinity of mutated DNMT3B (S270P) for the H3K36me3 epigenetic mark in the ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome. The model of the DNMT3A-DNMT3L heterotetramer in complex with a dinucleosome highlights the mechanism for recognition of nucleosome by DNMT3s and explains the periodicity of de novo DNA methylation.

Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B.,Rondelet G, Dal Maso T, Willems L, Wouters J J Struct Biol. 2016 Jun;194(3):357-67. doi: 10.1016/j.jsb.2016.03.013. Epub 2016 , Mar 15. PMID:26993463[10]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ Rondelet G, Dal Maso T, Willems L, Wouters J. Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. J Struct Biol. 2016 Jun;194(3):357-67. doi: 10.1016/j.jsb.2016.03.013. Epub 2016 , Mar 15. PMID:26993463 doi:http://dx.doi.org/10.1016/j.jsb.2016.03.013

5ciu, resolution 2.24Å

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