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New page: left|200px<br /> <applet load="2j2s" size="450" color="white" frame="true" align="right" spinBox="true" caption="2j2s" /> '''SOLUTION STRUCTURE OF THE NONMETHYL-CPG-BIN...
 
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[[Image:2j2s.gif|left|200px]]<br />
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'''SOLUTION STRUCTURE OF THE NONMETHYL-CPG-BINDING CXXC DOMAIN OF THE LEUKAEMIA-ASSOCIATED MLL HISTONE METHYLTRANSFERASE'''<br />


==Overview==
==Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase==
Methylation of CpG dinucleotides is the major epigenetic modification of, mammalian genomes, critical for regulating chromatin structure and gene, activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds, nonmethyl-CpG DNA, and is required for transformation by MLL fusion, proteins that commonly arise from recurrent chromosomal translocations in, infant and secondary treatment-related acute leukaemias. To elucidate the, molecular basis of nonmethyl-CpG DNA recognition, we determined the, structure of the human MLL CXXC domain by multidimensional NMR, spectroscopy. The CXXC domain has a novel fold in which two zinc ions are, each coordinated tetrahedrally by four conserved cysteine ligands provided, by two CGXCXXC motifs and two distal cysteine residues. We have identified, the CXXC domain DNA binding interface by means of chemical shift, perturbation analysis, cross-saturation transfer and site-directed, mutagenesis. In particular, we have shown that residues in an extended, surface loop are in close contact with the DNA. These data provide a, template for the design of specifically targeted therapeutics for poor, prognosis MLL-associated leukaemias.
<StructureSection load='2j2s' size='340' side='right'caption='[[2j2s]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2j2s]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J2S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J2S FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=2j2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j2s OCA], [https://pdbe.org/2j2s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j2s RCSB], [https://www.ebi.ac.uk/pdbsum/2j2s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j2s ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KMT2A_HUMAN KMT2A_HUMAN] Acute myeloid leukemia with 11q23 abnormalities;Precursor B-cell acute lymphoblastic leukemia;Wiedemann-Steiner syndrome;Acute biphenotypic leukemia;Acute undifferentiated leukemia;Bilineal acute leukemia. The disease is caused by mutations affecting the gene represented in this entry.  Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis.  A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.
== Function ==
[https://www.uniprot.org/uniprot/KMT2A_HUMAN KMT2A_HUMAN] Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref> <ref>PMID:12453419</ref> <ref>PMID:15960975</ref> <ref>PMID:19556245</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j2/2j2s_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2j2s ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Methylation of CpG dinucleotides is the major epigenetic modification of mammalian genomes, critical for regulating chromatin structure and gene activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds nonmethyl-CpG DNA, and is required for transformation by MLL fusion proteins that commonly arise from recurrent chromosomal translocations in infant and secondary treatment-related acute leukaemias. To elucidate the molecular basis of nonmethyl-CpG DNA recognition, we determined the structure of the human MLL CXXC domain by multidimensional NMR spectroscopy. The CXXC domain has a novel fold in which two zinc ions are each coordinated tetrahedrally by four conserved cysteine ligands provided by two CGXCXXC motifs and two distal cysteine residues. We have identified the CXXC domain DNA binding interface by means of chemical shift perturbation analysis, cross-saturation transfer and site-directed mutagenesis. In particular, we have shown that residues in an extended surface loop are in close contact with the DNA. These data provide a template for the design of specifically targeted therapeutics for poor prognosis MLL-associated leukaemias.


==Disease==
Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase.,Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ EMBO J. 2006 Oct 4;25(19):4503-12. Epub 2006 Sep 21. PMID:16990798<ref>PMID:16990798</ref>
Known diseases associated with this structure: Leukemia, myeloid/lymphoid or mixed-lineage OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=159555 159555]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2J2S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2J2S OCA].
</div>
<div class="pdbe-citations 2j2s" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase., Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ, EMBO J. 2006 Oct 4;25(19):4503-12. Epub 2006 Sep 21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16990798 16990798]
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Allen, M.D.]]
[[Category: Allen MD]]
[[Category: Bycroft, M.]]
[[Category: Bycroft M]]
[[Category: Grummitt, C.G.]]
[[Category: Grummitt CG]]
[[Category: Hilcenko, C.]]
[[Category: Hilcenko C]]
[[Category: Johnson, C.M.]]
[[Category: Johnson CM]]
[[Category: Tonkin, L.M.]]
[[Category: Tonkin LM]]
[[Category: Warren, A.J.]]
[[Category: Warren AJ]]
[[Category: Young-Min, S.]]
[[Category: Young-Min S]]
[[Category: ZN]]
[[Category: alternative splicing]]
[[Category: bromodomain]]
[[Category: chromatin]]
[[Category: chromosomal rearrangement]]
[[Category: cpg dinucleotide]]
[[Category: cxxc]]
[[Category: dna-binding]]
[[Category: hox genes]]
[[Category: mbd1]]
[[Category: metal-binding]]
[[Category: methylation]]
[[Category: mixed lineage leukaemia]]
[[Category: nuclear protein]]
[[Category: phosphorylation]]
[[Category: polymorphism]]
[[Category: proto-oncogene]]
[[Category: transcription]]
[[Category: transcription regulation]]
[[Category: zinc]]
[[Category: zinc binding]]
[[Category: zinc-finger]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:51:09 2007''

Latest revision as of 08:35, 15 May 2024

Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferaseSolution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase

Structural highlights

2j2s is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KMT2A_HUMAN Acute myeloid leukemia with 11q23 abnormalities;Precursor B-cell acute lymphoblastic leukemia;Wiedemann-Steiner syndrome;Acute biphenotypic leukemia;Acute undifferentiated leukemia;Bilineal acute leukemia. The disease is caused by mutations affecting the gene represented in this entry. Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.

Function

KMT2A_HUMAN Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.[1] [2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Methylation of CpG dinucleotides is the major epigenetic modification of mammalian genomes, critical for regulating chromatin structure and gene activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds nonmethyl-CpG DNA, and is required for transformation by MLL fusion proteins that commonly arise from recurrent chromosomal translocations in infant and secondary treatment-related acute leukaemias. To elucidate the molecular basis of nonmethyl-CpG DNA recognition, we determined the structure of the human MLL CXXC domain by multidimensional NMR spectroscopy. The CXXC domain has a novel fold in which two zinc ions are each coordinated tetrahedrally by four conserved cysteine ligands provided by two CGXCXXC motifs and two distal cysteine residues. We have identified the CXXC domain DNA binding interface by means of chemical shift perturbation analysis, cross-saturation transfer and site-directed mutagenesis. In particular, we have shown that residues in an extended surface loop are in close contact with the DNA. These data provide a template for the design of specifically targeted therapeutics for poor prognosis MLL-associated leukaemias.

Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase.,Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ EMBO J. 2006 Oct 4;25(19):4503-12. Epub 2006 Sep 21. PMID:16990798[5]

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

See Also

References

  1. ↑ Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ Jr, Tkachuk DC. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999 Oct;19(10):7050-60. PMID:10490642
  2. ↑ Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, Dubois G, Mazo A, Croce CM, Canaani E. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002 Nov;10(5):1119-28. PMID:12453419
  3. ↑ Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL, Roeder RG. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005 Jun 17;121(6):873-85. PMID:15960975 doi:10.1016/j.cell.2005.04.031
  4. ↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
  5. ↑ Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ. Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J. 2006 Oct 4;25(19):4503-12. Epub 2006 Sep 21. PMID:16990798
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